CN101896486A - Spiroindolinone derivatives - Google Patents
Spiroindolinone derivatives Download PDFInfo
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- CN101896486A CN101896486A CN2008801198987A CN200880119898A CN101896486A CN 101896486 A CN101896486 A CN 101896486A CN 2008801198987 A CN2008801198987 A CN 2008801198987A CN 200880119898 A CN200880119898 A CN 200880119898A CN 101896486 A CN101896486 A CN 101896486A
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- chloro
- phenyl
- piperidines
- indoles
- diketone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
There are provided compounds of the formula (I), and pharmaceutically acceptable salts and esters thereof, wherein W, V, X, Y, A, R and R' are as described herein, processes for making said compounds and methods for using them, in particular as anticancer agents.
Description
P53 is the tumor suppressor protein that plays a crucial role in preventing cancer development.Its protection cell integrity and the propagation of preventing the clone of cell permanent lesion by induced growth stagnation or apoptosis.On molecular level, p53 can activate one group to relate to the gene transcription factor of regulating cell cycle and apoptosis.P53 is the effective cell cycle inhibitor that closely regulated by MDM2.MDM2 and p53 form feedback control loop.MDM2 can and suppress the ability of its trans-activation p53-regulatory gene in conjunction with p53.In addition, the MDM2 mediation relies on the p53 degraded of ubiquitin.P53 can activate MDM2 genetic expression, increases the proteic cell levels of MDM2 thus.This feedback control loop guaranteed MDM2 and p53 in normal proliferative cell, all remain on low-level on.MDM2 also is the cofactor of E2F, and it plays a crucial role in Cycle Regulation.
The ratio of MDM2 and p53 (E2F) is subjected to unusual adjusting in many cancers.For example, confirmed the frequent damaged MDM2 proteolytic degradation that influenced of molecule that takes place on the p16INK4/p19ARF locus.The interaction that suppresses MDM2-p53 with wild type p53 in tumour cell should cause p53 accumulation, cell cycle arrest and/or apoptosis.Therefore, the MDM2 antagonist can provide new tool for cancer therapy as the single-activity agent or with other antitumor therapy coupling of wide spectrum.Be used to suppress the feasibility that the interactional different macromole instruments of MDM2-p53 (for example antibody, antisense oligonucleotide, peptide class) have confirmed this strategy by use.MDM2 also by as the conservative land of the p53 E2F-dependent transcription in conjunction with E2F and activating cells cyclin A, points out the MDM2 antagonist to have effect in the p53 mutant cells thus.
At J.Am Chem.Soc., in 2005,127,10130 at a series of Spiroindolinones that preceding disclose as the MDM2 antagonist.
The invention provides Spiroindolinone derivatives, they are the interactional micromolecular inhibitors of MDM2-p53.In acellular and test based on cell, compound exhibits of the present invention goes out to suppress the interaction of MDM2 albumen and p53-sample peptide.In the test based on cell, these compounds have proved machine-processed activity (mechanistic activity).Cancer cells is caused p53 albumen accumulation with the wild type p53 incubation, induce p21 gene that p53-regulates and cell cycle arrest, caused at external effective antiproliferative activity to the wild type p53 cell in G1 and G2 phase.On the contrary, under suitable compound concentration, in the cancer cells that has mutant p53, do not observe these activity.Therefore, the activity of MDM2 antagonist is relevant with its mechanism of action probably.These compounds can be carcinostatic agents effectively and optionally.
The present invention relates to the Spiroindolinone of formula (I):
Wherein
X is-Cl ,-F or-Br;
R is the phenyl of replacement or the heteroaryl of replacement, and wherein the heteroaryl of phenyl of Qu Daiing or replacement is selected from the group of being made up of following:
W is selected from the group of being made up of following :-F ,-Cl ,-Br ,-I, methyl, ethyl, cyclopropyl, cyano group, methoxyl group, methylol ,-COOMe, ethynyl ,-CF
3, vinyl, pseudoallyl, 1-proyl, 3-methyl isophthalic acid-butynyl, 3,3-dimethyl-ethyl acetylene base, 3-trifluoro ethynyl, phenyl, 2-furyl, 2-thienyl and 4-thiazolyl;
Y is a hydrogen ,-F ,-Cl or methyl;
V is a hydrogen ,-F ,-Cl or methyl;
A is selected from the group of being made up of following: key, O, NH, CH
2, C (=O), C (=O) NH, NHC (=O), NHC (=O) NH, S, S (=O)
2And O (CH
2)
n
N=1,2 or 3;
R ' is selected from the group of being made up of following: heterocycle, and the heterocycle of replacement, heteroaryl, the heteroaryl of replacement, aryl, the aryl of replacement, the cycloalkyl of replacement,
With-CR
1R
2C (=O) NR
3R
4, wherein
R
1, R
2Be hydrogen or low alkyl group, or can separate connection be selected from the ring texture of replacement or unsubstituted cycloalkyl with formation; And
R
3, R
4Be independently selected from the group of forming by following: hydrogen, low alkyl group, aryl, low-grade alkenyl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle of replacement, the cycloalkyl of cycloalkyl and replacement, condition are R
3, R
4Not all be hydrogen, or R
3/ R
4Can separate connection to form ring texture, described ring texture is selected from heteroaryl replacement or unsubstituted, cycloalkyl replacement or unsubstituted, cycloalkenyl group replacement or unsubstituted or replacement or unsubstituted heterocycle; With
Its pharmaceutical salts and ester.
Formula (I) compound preferably, W wherein, X, Y, A, R and R ' as mentioned above and V be hydrogen or F.
Formula (I) compound further preferably, W wherein, X, A, R and R ' as mentioned above, V is that hydrogen or F and Y are hydrogen or F.
Formula (I) compound further preferably also, X wherein, A, R and R ' as mentioned above, W is F, Cl, Br, I or ethynyl, Y are that hydrogen or F and V are hydrogen or F.
Formula (I) compound further preferably again, X wherein, R and R ' as mentioned above, W is F, Cl, Br, I or ethynyl, Y are hydrogen or F, V is that hydrogen or F and A are O or NH, condition is that V and Y not all are F.
Formula (I) compound further preferably again, wherein
R is the 3-chloro-phenyl-;
A is-O-or-NH-;
R ' is a piperidyl, tetrahydrochysene-pyranyl, and cyclohexyl, pyrrolidyl, phenyl, pyrazinyl and pyrazolyl, they all can be unsubstituted or be replaced by 1-5 substituting group; And
All remaining substituting groups have the above implication that provides.
Most preferred is those compounds of following formula:
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl methoxy base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl methoxy base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl methoxy base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl amino)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl amino)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-propionyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[1-(3-methylsulfonyl-propyl group)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methylsulfonyl-4-piperidyl oxygen base) phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methylsulfonyl-4-piperidyl oxygen base) phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-formyl-dimethylamino-4-piperidyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-bromo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-bromo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[6-(1-ethanoyl-4-piperidyl oxygen base)-3-bromo-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-ethyl-4-piperidyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-2-fluoro-6-(1-methyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-2-fluoro-6-(1-methyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-formyl-dimethylamino-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-formyl-dimethylamino-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-diethylamino formyl radical-4-piperidyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-iodo-2-[1-(tetramethyleneimine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[1-(tetramethyleneimine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-sec.-propyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[1-(2-oxo-imidazolidine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-3-chloro-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[6-(1-ethanoyl-4-piperidyl oxygen base)-3-chloro-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[3-chloro-6-(1-formyl-dimethylamino-4-piperidyl oxygen base)-2-fluoro-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[3-chloro-6-(1-methylamino formyl radical-4-piperidyl oxygen base)-2-fluoro-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-methylamino formyl radical-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-formyl-dimethylamino-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[1-(4-methylpiperazine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[1-(1-tetramethyleneimine-carbonyl)-4-piperidyl oxygen base]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[1-(1-tetramethyleneimine-carbonyl)-4-piperidyl oxygen base]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-formyl-dimethylamino-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-ethoxy carbonyl-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-ethoxy carbonyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-isobutyryl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-isopropoxy carbonyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-isobutyryl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-isopropoxy carbonyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2-[1-(2-hydroxyl-ethyl)-4-piperidyl oxygen base]-5-iodo-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-methoxycarbonyl methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-tertiary butyloxycarbonyl ylmethyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-hydroxycarbonyl group methyl-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-carbamyl ylmethyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(1-carbamyl ylmethyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-tertbutyloxycarbonyl-3-pyrrolidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-tertbutyloxycarbonyl-3-pyrrolidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-methoxyl group-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2,5-dimethyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-methoxyl group-4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-hydroxycarbonyl group-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[4-(2-hydroxyl-1,1-dimethyl-ethylamino formyl radical)-phenoxy group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[4-(2-tetramethyleneimine-1-base-ethylamino formyl radical)-phenoxy group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-formamyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-chloro-4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-5-iodo-phenyl } spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-5-iodo-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-5-chloro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl }-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-5-chloro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl }-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2,6-dimethyl-4-pyridyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(5-chloro-2-imidazoles-1-base-phenyl)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-methoxyl group-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-methoxyl group-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-methoxyl group-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-methoxycarbonyl-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-methoxycarbonyl-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-hydroxycarbonyl group-phenoxy group)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(4-formamyl-phenoxy group)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(4-formamyl-phenoxy group)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2,6-dimethyl-4-pyridyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2,6-dimethyl-4-pyridyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-fluoro-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-trifluoromethyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(4-trifluoromethyl-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(3-cyano group-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[4-(3-hydroxyl-propyl group)-phenoxy group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-cyano group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-cyano group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methylthio group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methyl sulphonyl-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methylsulfinyl-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-nitro-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(4-amino-phenoxy group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(4-amino-phenoxy group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(4-acetylamino-phenoxy group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-oxo-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3R, 4 ' S)-6-chloro-2 '-[2-chloro-6-(4-methoxyl group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(cis-4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(cis-4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(trans-the 4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(trans-the 4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-4-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-4-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-4-methyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' R)-6-chloro-4 '-(3-chloro-2-fluoro-phenyl)-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' R)-6-chloro-4 '-(3-chloro-4-fluoro-phenyl)-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[2-(4-ethanoyl-piperazine-1-yl)-1,1-dimethyl-2-oxo-oxyethyl group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[2-(4,4-two fluoro-piperidines-1-yl)-1,1-dimethyl-2-oxo-oxyethyl group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[1-methyl isophthalic acid-(2,2,2-three fluoro-ethylamino formyl radicals)-oxyethyl group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-formyl-dimethylamino-1-methyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-formyl-dimethylamino-2-methyl-propoxy-)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2,2-dimethyl-3-oxo-3-tetramethyleneimine-1-base-propoxy-)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(3-methyl-trimethylene oxide-3-ylmethoxy)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-bromo-2-(3-methyl-trimethylene oxide-3-ylmethoxy) phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-fluoro-benzyloxy)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(3-ethyl-trimethylene oxide-3-ylmethoxy)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-tertbutyloxycarbonyl-piperidin-4-yl oxygen base)]-5-trifluoromethyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-methyl-piperidin-4-yl amino)-phenyl]-6-chloro-4 '-(5-chloro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2-hydroxyl-oxyethyl group)-5-(2-thienyl)-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2-hydroxyl-oxyethyl group)-5-(2-furyl)-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2-hydroxyl-oxyethyl group)-5-phenyl-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(2-pyrazinyl oxygen base)-phenyl]-spiral shell-[3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-(2-furyl)-2-hydroxyl-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-(2-thio-furan base)-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-phenyl]-phenyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-(2-thiazolyl)-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-(2-thiazolyl)-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-2-[3-(tertbutyloxycarbonyl)-pyrroles's alkoxyl group (pyrolidinyloxy)]-5-chloro-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-(3-pyrroles's alkoxyl group)-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(3-methylsulfonyl-pyrroles's alkoxyl group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(3-ethylamino formyl radical-pyrroles's alkoxyl group)-phenyl }-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-3-pyrroles's alkoxyl group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[trans-4-(3-hydroxyl-1-methylsulfonyl-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-[5-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-fluoro-phenyl)-2 '-[5-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(1,1-dioxo-tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(cyclohexyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(cyclopentyloxy)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(cyclohexyl oxygen base-phenyl)]-4 '-(3-chloro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chlorine 2 '-[5-chlorine (chlororo)-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl]-4 '-(3-fluoro-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(1,1-dioxo-tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-fluoro-phenyl)-2 '-[5-fluoro-2-(4-fluoro-phenoxy group-phenyl)] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-4 '-(3-chloro-phenyl)-6-fluoro-2 '-[2-(2,4-two fluoro-phenyl oxygen bases)-5-fluoro-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[5-chloro-2-(2-chloro-6-fluoro-benzyloxy)-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[2-(4-cyano group-phenyl oxygen base)-5-fluoro-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[2-(4-cyano group-phenyl oxygen base)-5-fluoro-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-4 '-(3-chloro-phenyl)-2 '-[2-(4-cyano group-phenyl oxygen base)-5-fluoro-phenyl]-6-fluorine spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-fluoro-2-(4-methoxyl group-phenyl oxygen base)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-4 '-(3-chloro-phenyl)-6-fluoro-2 '-[5-fluoro-2-(4-methoxyl group-phenyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[5-fluoro-2-(4-methoxyl group-phenyl oxygen base)-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-[5-fluoro-2-(4-methoxyl group-phenyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' R)-6-chloro-4 '-(5-chloro-2-fluoro-phenyl)-2 '-[5-fluoro-2-(4-methoxyl group-phenyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-and 5-fluoro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group] phenyl }-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-4 '-(5-chloro-2-fluoro-phenyl)-2 '-and 5-fluoro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group] phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-fluoro-phenyl)-2 '-and 5-fluoro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group] phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-4 '-(3-chloro-phenyl)-6-fluoro-2 '-and 5-fluoro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group] phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-and 5-fluoro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group] phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-4 '-(5-chloro-2-trifluoromethyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(5-chloro-2-trifluoromethyl-phenyl)-2 '-[5-iodo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
(2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(5-chloro-2-trifluoromethyl-phenyl)-2 '-[2-(cyclohexyl oxygen base)-5-fluoro-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-fluoro-2-(cyclopentyloxy)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[2-(cyclohexyl oxygen base-5-iodine)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[2-(cyclohexyl oxygen base-5-fluorine)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[2-(cyclohexyl oxygen base-5-ethynyl)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-[2-(cyclohexyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-[2-(cyclohexyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[5-chloro-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[2-cyclohexyl oxygen base-5-fluoro-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-2 '-[5-chloro-2-(cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl)-6-fluorine spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-4 '-(3-chloro-phenyl)-2 '-[5-chloro-2-(tetrahydrochysene (tetrahedro)-thiapyran-4-base oxygen base-phenyl)]-6-fluorine spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(cyclohexyl oxygen base-phenyl)]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone and
Chirality (2 ' R, 3 ' R, 4 ' R)-6-chloro-4 '-(2,5-two fluoro-phenyl)-2 '-[5-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone.
In this specification sheets and claims, when indication, various groups, the group among the R ' particularly can be by 1-5, or preferred 1-3 substituting group replacement, described substituting group is independently selected from: low alkyl group, rudimentary-thiazolinyl, rudimentary-alkynyl, dioxo-rudimentary-alkylidene group (forming for example benzo dioxy base), halogen, hydroxyl ,-CN ,-CF
3,-NH
2,-N (H, rudimentary-alkyl) ,-N (rudimentary-alkyl)
2, aminocarboxyl, carboxyl ,-NO
2, rudimentary-alkoxyl group, sulfo--rudimentary-alkoxyl group; rudimentary-alkyl sulphonyl, amino-sulfonyl, rudimentary-alkyl-carbonyl; rudimentary-the alkyl-carbonyl oxygen base, rudimentary-alkoxy carbonyl, rudimentary-alkyl-carbonyl-NH; fluoro-is rudimentary-alkyl, and fluoro-is rudimentary-alkoxyl group, rudimentary-alkoxyl group-carbonyl-rudimentary-alkoxyl group; carboxyl-rudimentary-alkoxyl group; formamyl-rudimentary-alkoxyl group, hydroxyl-rudimentary-alkoxyl group ,-NH
2-rudimentary-alkoxyl group ,-N (H, rudimentary-alkyl)-rudimentary-alkoxyl group ,-N (rudimentary-alkyl)
2-rudimentary-alkoxyl group, benzyloxy-rudimentary-alkoxyl group, single-or amino-alkylsulfonyl of replacing of two-low alkyl group and can choose by halogen hydroxyl ,-NH wantonly
2,-N (H, rudimentary-alkyl) or-N (rudimentary-alkyl)
2Rudimentary-the alkyl that replaces.For aryl, heteroaryl and heterocyclic preferred substituents are halogens, lower alkoxy, low alkyl group and amino.
If alkyl, thiazolinyl, two ends of alkynyl or similar group are connected on the identical part, then can obtain ring texture, two hydrogen of wherein said part are by described alkyl, thiazolinyl, two terminal replacements of alkynyl or similar group, thus produce ring texture, as 1,2,3, the 4-tetraline, greatly the ring or spirocyclic compound.
Term " alkyl " is meant to have the 1 straight or branched saturated hydrocarbyl to about 20 carbon atoms.In certain embodiments, alkyl substituent can be a low-grade alkyl substituent.Term " low alkyl group " is meant the alkyl with 1 to 8 carbon atom, and in certain embodiments, is the alkyl with 1 to 4 carbon atom.The example of alkyl includes but not limited to, methyl, and ethyl, just-and propyl group, different-propyl group, just-and butyl, the second month in a season-butyl, tert-butyl, just-amyl group, and the second month in a season-amyl group.
As used herein, " cycloalkyl " means any stable monocycle or the multi-loop system of only being made up of carbon atom, its any ring is saturated, and term " cycloalkenyl group " means any stable monocycle or the multi-loop system of only being made up of carbon atom, and its at least one ring is that part is unsaturated.In both cases, by 5 to 12 lists that carbon atom is formed-or bicyclic system be particularly preferred.The example of cycloalkyl includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, adamantyl, the ring octyl group, bicyclic alkyl comprises double-octane as [2.2.2] double-octane or [3.3.0] double-octane, and bicyclic nonane is as [4.3.0] bicyclic nonane, with the dicyclo decane as [4.4.0] dicyclo decane (naphthane), or spirocyclic compound.The example of cycloalkenyl group includes but not limited to, cyclopentenyl or cyclohexenyl.
Term " thiazolinyl " is meant and contains two keys and have 2 to 8, the unsaturation straight or branched aliphatic hydrocarbyl of preferred 2 to 6 carbon atoms as used herein.The example of like this " thiazolinyl " is a vinyl, allyl group, pseudoallyl, 1-propenyl, 2-methyl isophthalic acid-propenyl, 1-butylene base, crotyl, the 3-butenyl, 2-ethyl-1-butylene base, 3-methyl-2-butene base, the 1-pentenyl, pentenyl, 3-pentenyl, the 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
Term " alkynyl " is meant and contains one three key and have 2 to 6, the unsaturation straight or branched aliphatic hydrocarbyl of preferred 2 to 4 carbon atoms as used herein.The example of like this " alkynyl " is an ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base and 5-hexin base.
Be meant fluorine as employed term " halogen " in definition, chlorine, iodine or bromine, preferred fluorine and chlorine.
" aryl " is meant the aromatic hydrocarbyl of univalent monocycle or dicyclo, the first aromatic ring of preferred 6-10 system.Preferred aryl groups includes but not limited to, phenyl, naphthyl, tolyl, and xylyl.
" heteroaryl " is meant single-or dicyclo, the aromatic hydrocarbon of preferred 5-10 unit, and wherein 1-4 carbon atom replaced by heteroatoms.Preferred heteroaryl includes but not limited to thienyl, furyl, indyl, pyrryl, pyridyl, pyrazinyl, pyrazolyl ， oxazolyl, thiazolyl (thiaxolyl), quinolyl, pyrimidyl, imidazoles and tetrazyl.
Under the situation of the aryl of dicyclo or heteroaryl, should be understood that a ring can be an aryl, and another is a heteroaryl, and two all is to replace or unsubstituted.
" heterocycle " be meant and replace or unsubstituted 5 to 8 yuan of lists-or the aromatics or the non-aromatic hydrocarbon of dicyclo, and wherein the heteroatoms that is selected from nitrogen, oxygen or the sulphur atom of 1 to 3 carbon atom replaces.Example comprises tetramethyleneimine-2-base; Tetramethyleneimine-3-base; Piperidyl; Morpholine-4-base etc.
" heteroatoms " is meant and is selected from N, the atom among O and the S.
" alcoxyl, alkoxyl group or lower alkoxy " is meant any above-mentioned low alkyl group that is connected on the Sauerstoffatom.Typical lower alkoxy comprises: methoxyl group, oxyethyl group, isopropoxy or propoxy-, butoxy etc.What further comprise in the implication of alkoxyl group is a plurality of alkoxyl group side chains, ethoxy ethoxy for example, methoxy ethoxy, methoxy ethoxy oxyethyl group etc.; With the alkoxyl group side chain that replaces, dimethylamino ethoxy for example, diethyl amino base oxethyl, dimethoxy-phosphoryl methoxy base etc.
" medicinal " is meant for the experimenter who gives specific compound it is acceptable and essentially no toxic on the pharmacology as pharmaceutical carrier, vehicle etc.
" pharmaceutical salts " is meant the biological effectiveness that keeps The compounds of this invention and characteristic and the conventional acid additive salt or the base addition salt that are formed by suitable nontoxicity organic acid or mineral acid or organic bases or mineral alkali.The example of acid salt comprise salt that those derive from mineral acid, all example hydrochloric acids, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, thionamic acid, phosphoric acid and nitric acid and those derive from organic acid, such as the salt of tosic acid, Whitfield's ointment, methylsulfonic acid, oxalic acid, succsinic acid, citric acid, oxysuccinic acid, lactic acid, fumaric acid, trifluoroacetic acid etc.The example of base addition salt comprises that those derive from salt, for example tetramethylammonium hydroxide of ammonium, potassium, sodium and quaternary ammonium hydroxide.With medical compounds (being medicine) chemically modified salify is physics and chemical stability, water absorbability, flowability and the deliquescent technology that the well-known acquisition compound of pharmacist improves.For example, referring to " pharmaceutical dosage form and drug delivery systems " such as Ansel (PharmaceuticalDosage Forms and Drug Delivery Systems) (the 6th edition 1995) 196 and 1456-1457 page or leaf.
Formula (I) compound and their salt have at least one unsymmetrical carbon, therefore can be used as racemic mixture or different steric isomer existence.Can separate various isomer by separation known method such as chromatography.The present invention includes all steric isomers.
Compound useful as drug of the present invention is particularly at cell proliferation disorders, more especially in the treatment of tumor disease or the control.These compounds can be used for the treatment of or the controlled entity knurl with the preparation that contains described compound, such as mammary gland, colon, lung and tumor of prostate.
Treatment significant quantity according to compound of the present invention is meant effective prevention, alleviation or improves disease symptoms or the consumption of the prolongation experimenter's survival time for the treatment of.The scope of determining to belong to art technology of treatment significant quantity.
Treatment significant quantity or dosage according to compound of the present invention can change in wide limit, and can measure according to mode well known in the art.Can comprise particular compound, route of administration, disease of being treated that is given and the patient who is treated according to the such dosage of individual need adjustment in every kind of particular case.In general, under the situation of or parenteral admin oral the grownup who body weight is about 70Kg, about 10mg is to about 10,000mg, and preferably about 200mg is extremely about 1, and dosage every day of 000mg should be suitable, but, when in case of necessity, can surpass the upper limit.Can with every day dosage with single dose or divided dose form administration, or for parenteral admin, can be with the continuous infusion form administration.
Preparation of the present invention comprises and is suitable for following those: oral, nose, part (comprising oral cavity and hypogloeeis), rectum, vagina and/or parenteral admin.Said preparation can exist with unit dosage form easily, and can be by any method preparation known in the pharmacopedics field.Can will change according to the main body that will treat and the ad hoc fashion of administration with the amount of solid support material combination with the activeconstituents of generation single dose form.Can will be to produce the formula I of result of treatment or the amount of II or III compound usually with the amount of the activeconstituents that produces the single dose form with solid support material combination.Usually, in 100 per-cents, the scope of this amount is about 1% to about 99% activeconstituents, and preferred about 5% to about 70%, most preferably from about 10% to about 30%.
Preparing these preparations or method for compositions may further comprise the steps: with compound of the present invention and carrier, and one or more optional ancillary component combinations.Usually, by with compound of the present invention and liquid vehicle or solid carrier in small, broken bits, or they both, evenly and combination nearly, then, if desired, with formed product.
The preparation that the present invention is suitable for oral administration can be following form: capsule, cachet, sachet, pill, tablet, lozenge (uses the matrix (flavored basis) of flavoring, normally sucrose and gum arabic or tragacanth gum), pulvis, granule or solution or the suspension agent of conduct in water-based or non-aqueous liquid, or as oil-in-water or water-in-oil liquid emulsion, or as elixir or syrup, or as pastille (use inert base (inert base), as gelatin and glycerine, or sucrose and gum arabic) and/or mouth wash shua etc., the The compounds of this invention that contains predetermined amount separately is as activeconstituents.Can also be with compound of the present invention as bolus (bolus), electuary or paste administration
" significant quantity " is meant effective prevention, alleviation or improves disease symptoms or the consumption of the prolongation experimenter's survival time for the treatment of.
" IC
50" be meant and suppress the concrete concentration of measuring active 50% needed specific compound.Wherein, IC
50Can measure as described later.
" medicinal ester " is meant the formula that has carboxyl or hydroxyl (I) compound of conventional esterification, this ester class kept the biological effectiveness of formula I compound and characteristic and in vivo (in vivo) be cracked into corresponding active carboxylic acid or alcohol respectively.
Can be synthetic according to formula of the present invention (I) compound according to following general scheme.For what those of ordinary skill in the art understood easily be, can be in general synthetic route by replacing reagent or reagent the compound in the preparation formula (I).By using the purifying of chiral chromatography, can obtain the compound in the formula (I) of or enrichment enantiomer pure as optically-active.
Scheme 1
Usually, the suitable aldehyde I that selects can with hexamethl disilamine base lithium, chlorine trialkyl silane and Acetyl Chloride 98Min. react in the multistep mode in single jar, generating 2-azepine-1,3-butadiene II (scheme I), and can be used as raw product and use.Ghosez, people such as L. have reported preparation and their application of formation heterocyclic (reference: Tetrahedron1995,11021 in azepine Diels-Alder reaction of 2-azepine-1,3-butadiene; J.Am.Chem.Soc.1999,2617; The document of wherein quoting).The suitable aldehyde I that selects is commercially available, or can be synthetic by various kinds of document method used for a long time.
Scheme 2
In the presence of alkali, under heating condition, at protonic solvent such as methyl alcohol, ethanol or aprotic solvent such as toluene, in the ortho-xylene, oxindole III can react with the suitable aldehydes or ketones that replaces, to obtain intermediate compound IV.Normally used alkali is tetramethyleneimine or piperidines.Intermediate compound IV can be protected, obtains intermediate V.Can be by the use Vinyl chloroformate, the dimethyl dicarbonate butyl ester, SEM-Cl, bromotoluene, and alkali such as 4-(dimethyl amine) pyridine (DMAP), triethylamine, NaH or LiH connect protecting group according to document program used for a long time.Greene, T.W. etc. are at " Protective Groups in OrganicSynthesis, second edition, John Wiley﹠amp; Described and summarized the example of protecting group formation and their deprotection among the Sons Inc..
Scheme 3
Intermediate V can react under 110 ℃ to 160 ℃ heating and anhydrous anhydrous condition in toluene or ortho-xylene with the 2-azepine-divinyl II of selection of preparation in the scheme 1, form intermediate VI and VI ', the primary product that they show as the racemic mixture form with two kinds of enantiomorphs.Remove protecting group (Pg) with afterreaction, obtain multiple R
2The compound VI I of derivatize and VII ' (scheme 3).At Pg is under the situation of Boc group, and the Boc group can prolong heating by trifluoroacetic acid or the temperature between 110 to 116 ℃ and remove.The racemic mixture of VI and VI ' or VII and VII ' can easily split into two kinds of chirality enantiomorphs by chirality superfluid chromatography (SFC) or chirality HPLC or chiral column chromatography.
Scheme 4
When R ' was the group of heterocycle or replacement, Compound I can be passed through reagent VIII, and compound R '-L, alkali such as K
2CO
3Or Cs
2CO
3At anhydrous N, the reaction in dinethylformamide or the N,N-dimethylacetamide, under heating condition and preparing.L is good leavings group such as Cl, Br, I, OMs or Ots.Compound VIII or commercially available or can be easily according to document program preparation used for a long time (scheme 4).Alternatively, raw material IX can react under the Mitsunobu reaction conditions with R '-OH, obtains intermediate X, and this intermediate X can be used LiAlH
4Or DIBAL is reduced into alcohol, uses MnO then
2Or oxidation under the Swern oxidizing condition, obtain intermediate compound I (scheme 5).
Scheme 5
Scheme 6
Working as R ' is to be selected from aryl, and when the aryl of replacement, the heteroaryl of heteroaryl or replacement, intermediate compound I can the coupled reaction preparation (scheme 6) under heating condition by compounds X I and R '-OH.
When W is an ethynyl, the 1-proyl, pseudoallyl, the 1-proyl, 3-methyl isophthalic acid-butynyl, 3,3-dimethyl-ethyl acetylene base during 3-trifluoro ethynyl, can adopt alternative synthetic method, to obtain compound or XII-a or XII-b.Typically, at first having the similar XII-a of the phenyl of corresponding iodo-or bromo-replacement according to the preparation of the method among the scheme 1-3, then is the Sonogashira reaction of catalytic palladium mediation, obtains those XII-b (scheme 7).
W=I or Br R
2=H, Me, CF
3, ethyl, sec.-propyl, cyclopropyl
The tertiary butyl
XII-a XII-b
Reagent and condition
1) if R
2=Me, Et, iPr, cyclopropyl, tBu, CF
3,
Cul, NEt
3, PdCl
2(PPh
3)
2(catalyzer) 100 ℃
2) if R
2=H:Cul, NEt
3, trimethyl silyl acetylene, PdCl
2(PPh
3)
2(catalyzer) 100 ℃
NaOH/MeOH then, room temperature
Scheme 7
At first prepare similar XIII-a according to the method among the scheme 1-3, then nitroreduction is become the amido among the XIII-b, reductive amination process obtains XIII-c (scheme 8) then.Similarly XIV-b can prepare according to the program in the scheme 9.
Reagent and condition:
1) Zn, NH
4Cl, or Ni in Ruan, NH
2NH
2
2) R ' C (=O) R ", catalyzer tosic acid, o-Xylol, heating
3)NaCNBH
3，MeOH
Scheme 8
A=Br or I
XIV-a XIV-b
Reagent and condition:
Cul, Cs
2CO
3, NHR ' R ", N, N, N ', N '-Tetramethyl Ethylene Diamine, heating, DMF
Scheme 9
Provide the following example and reference to help understanding the present invention, true scope of the present invention is listed in the appended claim.
Embodiment 1a
Preparation intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-1, the 3-dihydro-indol-2-one
M.W.290.15?C
15H
9Cl
2NO
(16.2g, 92mmol) (12.9g 92mmol) in (Aldrich) mixture in methyl alcohol (109mL), drips tetramethyleneimine (6.55g, 92mmol) (Aldrich) for (Crescent) and 3-chloro-phenyl aldehyde to 6-chlorine oxindole.Then mixture is heated 3h at 70 ℃.After being cooled to 4 ℃, mixture to be filtered, and the throw out that obtains is collected, drying obtains E/Z-6-chloro-3-(3-chloro-benzylidene)-1, and 3-dihydro-indol-2-one mixture is glassy yellow solid (yield 25.2g, 95%).
Embodiment 1b
Preparation intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-t-butyl formate
M.W.390.27?C
20H
17Cl
2NO
3
The E/Z-6-chloro-3-that in embodiment 5a at room temperature, prepares (3-chloro-benzylidene)-1,3-dihydro-indol-2-one (1g, 3.4mmol) in the solution in methylene dichloride (50mL), add dimethyl dicarbonate butyl ester (1.5g, 6.9mmol) (Aldrich), then add 4-dimethylaminopyridine (1g, 8.2mmol).With reaction mixture at stirring at room 1h.Then mixture is concentrated, and resistates is passed through chromatography purification, obtain E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-t-butyl formate is orange solids (yield 1.3g, 96%).
Embodiment 1c
Preparation intermediate 4-(2-formyl radical-4-iodo-phenoxymethyl)-piperidines-1-t-butyl formate
M.W.445.30?C
18H
24INO
4
(2g, 8.2mmol) (Aldrich) in the solution in the dinethylformamide (20mL), adds anhydrous K at N to 5-iodine salicylic aldehyde
2CO
3(1.15g, 8.2mmol) and 4-brooethyl-piperidines-1-t-butyl formate (2.3g, 8.2mmol, Pharmacore).Reaction mixture is heated 18h at 60 ℃.With thick product cool to room temperature, with ethyl acetate dilution, water, salt water washing.Separate organic layer, use MgSO
4Drying concentrates, and obtains 4-(2-formyl radical-4-iodo-phenoxymethyl)-piperidines-1-t-butyl formate (yield 2.3g, 63%).
Embodiment 1d
Preparation intermediate 1-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl methoxy base)-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.558.54?C
23H
351N
2O
4Si
Under nitrogen, in 1,1,1,3,3 of room temperature, (0.8g 5mmol) is just adding in (Aldrich)-butyllithium (2.5M, 2mL, 5mmol) (Aldrich) the 3-hexamethyldisilazane.With reaction mixture stirring at room 10 minutes.Add exsiccant tetrahydrofuran (THF) (20mL) then, then be added in 4-(2-formyl radical-4-iodo-phenoxymethyl)-piperidines-1-t-butyl formate of preparing among the embodiment 1c (2.3g, 5mmol).With mixture behind stirring at room 0.5h, drip trimethylsilyl chloride (0.55g, 5mmol) (Aldrich).Then mixture temperature is reduced to 0 ℃ on the cooling ice bath.(0.7g 6.8mmol), follows dripping acetyl chloride (0.5g, 6.8mmol) solution in diethyl ether (40mL) to disposable adding triethylamine in this mixture.Remove cooling bath, and with mixture at stirring at room 1h.Mixture is filtered on diatomite under nitrogen fast, and filtrate is under reduced pressure concentrated, obtain thick 1-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl methoxy base)-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1, the 3-divinyl, be yellow oil, and without being used for next step with being further purified.
Embodiment 1e
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl methoxy base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.776.49?C
35H
36Cl
2IN
3O
5
To the 1-[2-that in embodiment 1d, prepares (1-(tertbutyloxycarbonyl)-4-piperidyl methoxy base)-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1, in the solution of 3-divinyl (5mmol) in toluene (20mL), be added in E/Z-6-chloro-3-(3-chlorine the benzylidene)-2-oxo-2 for preparing among the embodiment 1b, 3-dihydro-indoles-1-t-butyl formate (0.7g, 1.8mmol).Reaction mixture is heated 5h in 150 ℃ under nitrogen.Behind the solution cool to room temperature, add methyl alcohol (10mL) and mixture is concentrated.Resistates is passed through chromatography purification (EtOAc: CH
2Cl
2=1; 1, EtOAc then), obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl methoxy base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is yellow solid (yield 0.89g, 64%).
HRMS (ES
+) m/z is to C
35H
36Cl
2IN
3O
5+ H[(M+H)
+] calculated value: 776.1150.Actual measurement: 776.1154.
Embodiment 2
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl methoxy base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.674.62?C
37H
37Cl
2N
3O
5
To the racemize that in embodiment 1e, prepares (2 ' R, 3R, 4 ' S)-2 '-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl methoxy base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.89g, 1.15mmol) add trimethyl silyl acetylene (0.23g in the solution in anhydrous tetrahydro furan (30mL), 2.3mmol) (Aldrich), CuI (0.44g, 2.3mmol) (Aldrich) and triethylamine (0.13g, 2.3mmol).With the mixture 5min that under nitrogen, outgases, add dichloro two (triphenylphosphine) palladium (0) (160mg, 0.23mmol) (Strem), and reaction mixture heated 2h at 80 ℃ under nitrogen then.Filter with the reaction mixture cool to room temperature and by the short pad of silica gel, silica gel is washed with ethyl acetate.Filtrate is concentrated.In resistates, add the methyl alcohol (20mL) and the NaOH aqueous solution (1N, 10mL).Mixture at stirring at room 2h, is distributed between ethyl acetate and water then.Separate organic layer, and with the water layer ethyl acetate extraction.Merge organic layer, use MgSO
4Dry and concentrated.With resistates chromatography (EtOAc: purifying hexane=2: 1), obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-tertbutyloxycarbonyl)-4-piperidyl methoxy base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (yield 0.24g, 31%).
HRMS (ES
+) m/z is to C
37H
37Cl
2N
3O
5+ H[(M+H)
+] calculated value: 674.2183.Actual measurement: 674.2185.
Embodiment 3a
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-piperidyl methoxy base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.574.51?C
32H
29Cl
2N
3O
3
Racemize (2 ' the R that will in embodiment 2, prepare, 3R, 4 ' S)-2 '-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl methoxy base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.22g, 0.32mmol) be dissolved in formic acid (88%, Alfa) in.At stirring at room 1h, pour reaction mixture into saturated NaHCO then
3In the aqueous solution.With the mixture ethyl acetate extraction.Separate organic layer, MgSO is used in water, salt water washing
4Dry and concentrated, obtain thick racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-piperidyl methoxy base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield: 0.19g, 100%).
Embodiment 3b
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl methoxy base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.616.54?C
34H
31Cl
2N
3O
4
To the racemize that in embodiment 3a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-piperidyl methoxy base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.19g, 0.32mmol) in the solution in methylene dichloride (10mL), add anhydrous K
2CO
3(0.2g, 1.5mmol) and diacetyl oxide (50mg, 0.49mmol).With reaction mixture at stirring at room 1h.Mixture is diluted water, salt water washing with ethyl acetate.Separate organic layer, use MgSO
4Drying concentrates.Resistates is passed through chromatography (EtOAc: MeOH=92: 8) purifying; obtain racemize (2 ' R; 3R; 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl methoxy base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.12g, 61%).
HRMS (ES
+) m/z is to C
34H
31Cl
2N
3O
4+ H[(M+H)
+] calculated value: 616.1765.Actual measurement: 616.1764.
Embodiment 4a
Preparation intermediate 4-(2-formyl radical-4-iodo-phenoxy group)-piperidines-1-t-butyl formate
M.W.431.21?C
17H
22INO
4
(3g, 12.1mmol) (Aldrich) in the solution in the dinethylformamide (20mL), adds anhydrous K at N to 5-iodine salicylic aldehyde
2CO
3(5g, 36.3mmol) and 4-(toluene-4-alkylsulfonyl oxygen base)-piperidines-1-t-butyl formate (5.4g, 18.1mmol, ASTATECH).Reaction mixture is heated 18h at 60 ℃.With the mixture cool to room temperature,, wash with water with the ethyl acetate dilution.Separate organic layer, the water layer ethyl acetate extraction.Merge organic layer, MgSO is used in water, salt water washing
4Drying and concentrated obtains thick 4-(2-formyl radical-4-iodo-phenoxy group)-piperidines-1-t-butyl formate, is yellow oil (yield 4.38g, 84%).
Embodiment 4b
Preparation intermediate 1-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.544.51?C
22H
331N
2O
4Si
With with in the similar mode of method described in the embodiment 1d; the 4-that will in embodiment 4a, prepare (2-formyl radical-4-iodo-phenoxy group)-piperidines-1-t-butyl formate (22g; 51mmol) replace 4-(2-formyl radical-4-iodo-phenoxymethyl)-piperidines-1-t-butyl formate as raw material; with 1; 1,3,3; 3-hexamethyldisilazane (13.4mL; 51mmol), just-butyllithium (2.5M, 25.7mL; 51mmol); trimethylsilyl chloride (8.09mL, 51mmol), triethylamine (11.7mL; 66mmol) and Acetyl Chloride 98Min. (5.88mL; 66mmol) reaction obtains thick 1-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene; be yellow jelly, and without being used for next step with being further purified.
Embodiment 4c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.762.47?C
34H
34Cl
2IN
3O
5
With with in the similar mode of method described in the embodiment 1e, the E/Z-6-chloro-3-that will in embodiment 5b, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-t-butyl formate (14g, 36mmol) with 1-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen the base)-5-iodo-phenyl that in embodiment 4b, prepares]-3-trimethylsiloxy-2-azepine-1,3-divinyl (66mmol) reacts 6h in 140 ℃ in toluene (200mL), obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 4.1g, 15%)
HRMS (ES
+) m/z is to C
34H
34Cl
2IN
3O
5+ H[(M+H)
+] calculated value: 762.0993.Actual measurement: 762.0993.
Embodiment 5a
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.662.36?C
29H
26Cl
2IN
3O
3
Trifluoroacetic acid (30mL) is added in the racemize (2 ' R for preparing among the embodiment 4c, 3R, 4 ' S)-2 '-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2, (2g is 2.62mmol) in the solution in methylene dichloride (30mL) for 6 ' (1H)-diketone.With mixture at stirring at room 1h.With solvent vacuum-evaporation, add saturated NaHCO then
3The aqueous solution.With the mixture ethyl acetate extraction.Separate organic layer, MgSO is used in water and salt water washing
4Drying and concentrated obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is yellow solid (yield: 1.7g, 98%).
Embodiment 5b
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.704.39?C
31H
28Cl
2IN
3O
4
To the racemize that in embodiment 5a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2, (50mg 0.076mmol) in the solution in anhydrous tetrahydro furan (2mL), adds triethylamine (11.4mg to 6 ' (1H)-diketone, 0.114mmol) and Acetyl Chloride 98Min. (6.5mg, 0.083mmol).With reaction mixture at stirring at room 0.5h.Mixture is diluted with ethyl acetate, wash with water.Separate organic layer, and with the water layer ethyl acetate extraction.Merge organic layer, use the salt water washing, use MgSO
4Drying concentrates.With resistates and methylene dichloride and hexane grinding; obtain racemize (2 ' R; 3R; 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 43mg, 81%).
HRMS (ES
+) m/z is to C
31H
28Cl
2IN
3O
4+ H[(M+H)
+] calculated value: 704.0575.Actual measurement: 704.0573.
Embodiment 5c
Preparation chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.704.39?C
31H
28Cl
2IN
3O
4
By chirality SFC from racemize (2 ' R; 3R; 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (64mg) separates two enantiomorphs; chirality (2 ' R is provided; 3R; 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; be white solid (20mg; 31%) (RO5219461-000) and chirality (2 ' S, 3S, 4 ' R)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone, for white solid (17mg, 27%) (RO5219462-000).
Embodiment 6a
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.602.52?C
33H
29Cl
2N
3O
4
To the racemize that in embodiment 5b, prepares (2 ' R; 3R; 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines] (0.1g is 0.14mmol) at anhydrous N for-2,6 ' (1H)-diketone; add trimethyl silyl acetylene (0.2mL in the solution in the dinethylformamide (1mL); 1.4mmol) (Aldrich), CuI (2mg) (Aldrich) and triethylamine (0.59mL, 4.2mmol).With the mixture 5min that under nitrogen, outgases, add then dichloro two (triphenylphosphine) palladium (0) (10mg, 0.014mmol) (Strem) and with reaction mixture under nitrogen in 90 ℃ of heating 2h.With the mixture cool to room temperature, between ethyl acetate and water, distribute.Separate organic layer, and with the water layer ethyl acetate extraction.Merge organic layer, use the salt water washing, use MgSO
4Drying and concentrated.Resistates by chromatography purification, is obtained yellow solid (50mg).This solid is dissolved in the methyl alcohol (10mL), and the adding NaOH aqueous solution (1N, 1.2mL).Mixture at stirring at room 2h, is distributed between ethyl acetate and water then.Separate organic layer, use MgSO
4Dry and concentrated.With the resistates chromatography purification; obtain racemize (2; R; 3R; 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; be yellow solid (yield 17mg, 20%).
HRMS (ES
+) m/z is to C
33H
29Cl
2N
3O
4+ H[(M+H)
+] calculated value: 602.1608.Actual measurement: 602.1610.
Embodiment 6b
Preparation chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.602.52?C
33H
29Cl
2N
3O
4
By chirality SFC; from the racemize (2 ' R that among embodiment 6a, prepares; 3R; 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (70mg) separates two enantiomorphs; chirality (2 ' R is provided; 3R; 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (15mg; 22%) (RO5208434-000); and chirality (2 ' S, 3S, 4 ' R)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone, for white solid (30mg, 44%) (RO5208432-000).
Embodiment 7
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.676.38?C
30H
28Cl
2IN
3O
3
To the racemize that in embodiment 5a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2, (0.2g 0.3mmol) in the solution in methyl alcohol (10mL), adds formalin (37wt% to 6 ' (1H)-diketone, Aldrich) (0.045mL, 0.6mmol) and NaCNBH
3(28mg, 0.45mmol).Reaction mixture at stirring at room 1h, is concentrated then.Resistates is distributed between ethyl acetate and water.Separate organic layer, and with the water layer ethyl acetate extraction.Merge organic layer, use the salt water washing, use MgSO
4Drying and concentrated.Resistates is passed through chromatography (EtOAc: purifying triethylamine=10: 3.5), obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (yield 70mg, 35%).
HRMS (ES
+) m/z is to C
30H
28Cl
2IN
4O
4+ H[(M+H)
+] calculated value: 676.0625.Actual measurement: 676.0628.
Embodiment 8a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.574.51?C
32H
29Cl
2N
3O
3
With with in the similar mode of method described in the embodiment 6a, make the racemize (2 ' R of preparation in embodiment 7,3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.35g, 0.51mmol) and trimethyl silyl acetylene (0.51mL, 5.1mmol), CuI (10mg), triethylamine (1.56g, 15.3mmol), (36mg 0.051mmol) at anhydrous N, reacts in the dinethylformamide with dichloro two (triphenylphosphine) palladium (0), in methyl alcohol, handle then with the NaOH aqueous solution, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-ethynyl-4-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is pale solid (yield 0.115g, 39%)
Embodiment 8b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.574.51?C
32H
29Cl
2N
3O
3
By chirality SFC, from the racemize (2 ' R that among embodiment 8a, prepares, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (100mg) separates two enantiomorphs, chirality (2 ' R is provided, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be yellow solid (35mg, 35%) (RO5212439-000), and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for yellow solid (40mg, 40%) (RO5212440-000).
HRMS (ES
+) m/z is to C
32H
29Cl
2N
3O
3+ H[(M+H)
+] calculated value: 574.1659.Actual measurement: 574.1656.
Embodiment 9a
Preparation intermediate 5-iodo-2-nitro-phenyl aldehyde
M.W.277.02?C
7H
4INO
3
To 0 ℃ 5-iodo-2-nitrobenzoic acid (37g, 126mmol) in (APIN) solution in anhydrous tetrahydro furan (200mL), drip the borine tetrahydrofuran (THF) (1M, 360mL, 360mmol).Then with reaction mixture at stirring at room 24h.Mixture is concentrated and resistates is distributed between ethyl acetate and water.Separate organic layer, use the salt water washing, use MgSO
4Drying concentrates, and grinds.Collecting precipitation thing 5-iodo-2-nitro-phenyl)-and methyl alcohol, be yellow solid (20g, 57%).
Described solid (5.5g) is dissolved in methylene dichloride (100mL), and adds activatory MnO
2(15g).Then mixture is heated 4h under refluxing, cool to room temperature, and by the short pad filtration of diatomite.Filtrate is concentrated, obtain 5-iodo-2-nitro-phenyl aldehyde, be yellow solid (yield 4.2g, 76%).
Embodiment 9b
Preparation intermediate 1-(5-iodo-2-nitrophenyl)-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.390.26 C
12H
15IN
2OSi
With with in the similar mode of method described in the embodiment 1d, the 5-iodo-2-nitrobenzaldehyde (4.2g that will in embodiment 9a, prepare, 15mmol) replace 2-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group as raw material]-5-iodo-phenyl aldehyde, with 1,1,3,3,3-hexamethyldisilazane (2.4g, 15mmol), just-butyllithium (2.5M, 6mL, 15mmol), trimethylsilyl chloride (1.6g, 15mmol), triethylamine (2.1g, 20mmol) and Acetyl Chloride 98Min. (1.5g, 20mmol) reaction obtains thick 1-(5-iodo-2-nitrophenyl)-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 9c
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-iodo-2-nitrophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.608.22 C
24H
16Cl
2IN
3O
4
To the 1-that in embodiment 9b, prepares (5-iodo-2-nitrophenyl)-3-trimethylsiloxy-2-azepine-1, in the solution of 3-divinyl (15mmol) in toluene (40mL), be added in E/Z-6-chloro-3-(3-chlorine the benzylidene)-2-oxo-2 for preparing among the embodiment 1b, 3-dihydro-indoles-1-t-butyl formate (2g, 5mmol).Reaction mixture is stirred 3h in 150 ℃ under nitrogen.With solution cool to room temperature and concentrated.Be dissolved in resistates in the methylene dichloride (20mL) and adding trifluoroacetic acid (10mL).Reaction mixture behind stirring at room 0.5h, is concentrated mixture.With resistates at saturated NaHCO
3Distribute between solution and the ethyl acetate.With the water layer ethyl acetate extraction.With the organic layer Na that merges
2SO
4Dry and concentrated.Resistates is passed through chromatography (EtOAc: CH
2Cl
2=1: 4) purifying, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-iodo-2-nitrophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be yellow solid (yield 1.8g, 59%)
HRMS (ES
+) m/z is to C
24H
16Cl
2IN
3O
4+ H[(M+H)
+] calculated value: 607.9636.Actual measurement: 607.9638.
Embodiment 9d
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-2 '-(2-amino-5-iodophenyl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.578.24 C
24H
18Cl
2IN
3O
2
To the racemize that in embodiment 9c, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-iodo-2-nitrophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2, (0.7g 1.15mmol) in the suspension in methyl alcohol (50mL), adds NH to 6 ' (1H)-diketone
4The Cl aqueous solution (0.61g, 11.5mmol, 20mL), then add the Zn powder (0.75g, 11.5mmol).Reaction mixture at stirring at room 1h, is filtered by the short pad of diatomite then.Filtrate is concentrated, with ethyl acetate and dichloromethane extraction.Merge organic layer, use MgSO
4Drying and concentrated.With resistates chromatography (EtOAc, EtOAc then: MeOH=19; 1) purifying obtains racemize (2 ' R, 3R, 4 ' S)-2 '-(2-amino-5-iodophenyl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, is white solid (yield 0.41g, 61%)
HRMS (ES
+) m/z is to C
24H
18Cl
2IN
3O
2+ H[(M+H)
+] calculated value: 577.9894.Actual measurement: 577.9894.
Embodiment 9e
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl amino)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.703.40 C
31H
29Cl
2IN
4O
3
To the racemize that in embodiment 9d, prepares (2 ' R; 3R; 4 ' S)-2 '-(2-amino-5-iodophenyl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; (0.16g 0.28mmol) in the suspension in ortho-xylene (50mL), adds 1-ethanoyl-4-piperidone (0.14g to 6 ' (1H)-diketone; 1mmol, Lancaster) and a hydration right-toluenesulphonic acids (15mg).With reaction mixture (180 ℃) heating 8h, cool to room temperature and concentrated then under refluxing.In resistates, add methyl alcohol (10mL), acetate (1mL), and NaCNBH
3(0.1g, 1.6mmol).Reaction mixture at stirring at room 1h, is concentrated then.Resistates is distributed between ethyl acetate and water.Separate organic layer, with the water layer ethyl acetate extraction.Merge organic layer, use the salt water washing, use MgSO
4Drying and concentrated.Resistates is passed through chromatography (EtOAc: MeOH=9: 1) purifying; obtain racemize (2 ' R; 3R; 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl amino)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.15g, 76%)
HRMS (ES
+) m/z is to C
31H
29Cl
2IN
4O
3+ H[(M+H)
+] calculated value: 703.0734.Actual measurement: 703.0730.
Embodiment 10
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl amino)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.601.53 C
33H
30Cl
2N
4O
3
With with in the similar mode of method described in the embodiment 2; make the racemize (2 ' R that in embodiment 9e, prepares; 3R; 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl amino)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (0.14g; 0.2mmol) and trimethyl silyl acetylene (39mg; 0.4mmol), CuI (76mg, 0.4mmol); triethylamine (40mg; 0.4mmol) and dichloro two (triphenylphosphine) palladium (0) (30mg 0.04mmol) reacts in anhydrous tetrahydro furan; in methyl alcohol, handle then with the NaOH aqueous solution; obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl amino)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (yield 0.25g, 84%)
HRMS (ES
+) m/z is to C
33H
30Cl
2N
4O
3+ H[(M+H)
+] calculated value: 601.1768.Actual measurement: 601.1767.
Embodiment 11a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-propionyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.718.42?C
32H
30Cl
2IN
3O
4
With with in the similar mode of method described in the embodiment 5b; make propionyl chloride (15.4mg; 0.17mmol) replacing acetyl chloride is as raw material; with the racemize that in embodiment 5a, prepares (2 ' R; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (0.1g; 0.15mmol) and triethylamine in tetrahydrofuran (THF), react; obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-propionyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is yellow solid (yield 0.11g, 100%).
Embodiment 11b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-propionyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.616.54?C
34H
31Cl
2N
3O
4
With with in the similar mode of method described in the embodiment 6a; racemize (2 ' the R that will in embodiment 11a, prepare; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-propionyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (0.1g; 0.14mmol) and trimethyl silyl acetylene (0.14g; 1.4mmol); CuI (2mg), and triethylamine (0.42g, 4.17mmol); with dichloro two (triphenylphosphine) palladium (0) (9.8mg; 0.014mmol) at anhydrous N, react in the dinethylformamide, in methyl alcohol, handle then with the NaOH aqueous solution; obtain racemize racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-propionyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (yield 10mg)
HRMS (ES
+) m/z is to C
34H
31Cl
2N
3O
4+ H[(M+H)
+] calculated value: 616.1765.Actual measurement: 616.1760.
Embodiment 12a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-iodo-2-[1-(3-methylsulfonyl-propyl group)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.782.53?C
33H
34Cl
2IN
3O
5S
To the racemize that in embodiment 5a, prepares (2 ' R; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; (0.1g 0.15mmol) in the solution in ethanol (2mL), adds methylsulfonic acid 3-methylsulfonyl-propyl ester (54mg to 6 ' (1H)-diketone; 0.25mmol) (WO2001062668) and triethylamine (0.031mL, 0.225mmol).At 68 ℃ of heating 18h, cool to room temperature is with concentrated then with reaction mixture.Resistates is distributed between ethyl acetate and water.Separate organic layer, and with the water layer ethyl acetate extraction.Merge organic layer, use the salt water washing, use MgSO
4Dry; with concentrated; obtain rough racemize (2 ' R; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-iodo-2-[1-(3-methylsulfonyl-propyl group)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be faint yellow solid (yield 0.1g)
Embodiment 12b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[1-(3-methylsulfonyl-propyl group)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.680.65?C
35H
35Cl
2N
3O
5S
With with in the similar mode of method described in the embodiment 6a; make the racemize (2 ' R that in embodiment 12a, prepares; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-iodo-2-[1-(3-methylsulfonyl-propyl group)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (0.1g; 0.13mmol) and trimethyl silyl acetylene (0.13mL; 1.3mmol), CuI (3mg), triethylamine (0.39g; 3.84mmol); (8.9mg 0.013mmol) at anhydrous N, reacts in the dinethylformamide with dichloro two (triphenylphosphine) palladium (0); in methyl alcohol, handle then with the NaOH aqueous solution; obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-{ 5-ethynyl-2-[1-(3-methylsulfonyl-propyl group)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is brown solid (yield 39mg, 45%)
HRMS (ES
+) m/z is to C
35H
35Cl
2N
3O
5S+H[(M+H)
+] calculated value: 680.1747.Actual measurement: 680.1746.
Embodiment 13a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-methylsulfonyl-4-piperidyl oxygen base) phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.740.45?C
30H
28Cl
2IN
3O
5S
To the racemize that in embodiment 5a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2, (0.1g 0.15mmol) in the solution in methylene dichloride (2mL), adds triethylamine (18.3mg to 6 ' (1H)-diketone, 0.18mmol) and methylsulfonyl chloride (19.1mg, 0.165mmol).With reaction mixture at stirring at room 0.5h.Mixture is diluted with methylene dichloride, wash with water.Separate organic layer, use the salt water washing, use MgSO
4Drying concentrates, and obtains racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-methylsulfonyl-4-piperidyl oxygen base) phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is yellow solid (yield 0.11g, 99%).
Embodiment 13b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methylsulfonyl-4-piperidyl oxygen base) phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.638.57?C
32H
29Cl
2N
3O
5S
With with in the similar mode of method described in the embodiment 6a; make the racemize (2 ' R that in embodiment 13a, prepares; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-methylsulfonyl-4-piperidyl oxygen base) phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (0.11g; 0.15mmol) and trimethyl silyl acetylene (0.15mL; 1.49mmol), CuI (3mg), triethylamine (0.45g; 4.46mmol); (10mg 0.015mmol) at anhydrous N, reacts in the dinethylformamide with dichloro two (triphenylphosphine) palladium (0); in methyl alcohol, handle then with the NaOH aqueous solution; obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methylsulfonyl-4-piperidyl oxygen base) phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is faint yellow solid (yield 51mg, 54%)
HRMS (ES
+) m/z is to C
32H
29Cl
2N
3O
5S+H[(M+H)
+] calculated value: 638.1278.Actual measurement: 638.1274.
Embodiment 13c
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methylsulfonyl-4-piperidyl oxygen base) phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.638.57?C
32H
29Cl
2N
3O
5S
By chirality SFC; from the racemize (2 ' R that among embodiment 13b, prepares; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methylsulfonyl-4-piperidyl oxygen base) phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (100mg) separates two enantiomorphs; chirality (2 ' R is provided; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methylsulfonyl-4-piperidyl oxygen base) phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (31mg; 31%) (RO5246414-000); and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methylsulfonyl-4-piperidyl oxygen base) phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone, for white solid (34mg, 34%) (RO5216413-000).
Embodiment 14a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-formyl-dimethylamino-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.733.44?C
32H
31Cl
2IN
4O
4
With with in the similar mode of method described in the embodiment 5b; with dimethylcarbamyl chloride (17.9mg; 0.17mmol) replacing acetyl chloride is as raw material; with the racemize that in embodiment 5a, prepares (2 ' R; 3R; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (0.1g; 0.15mmol) and triethylamine in tetrahydrofuran (THF), react; obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-formyl-dimethylamino-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is yellow solid (yield 0.1g, 91%).
Embodiment 14b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-formyl-dimethylamino-4-piperidyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.631.56?C
34H
32Cl
2N
4O
4
With with in the similar mode of method described in the embodiment 6a; make the racemize (2 ' R that in embodiment 14a, prepares; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-formyl-dimethylamino-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (0.1g; 0.14mmol) and trimethyl silyl acetylene (0.13g; 1.4mmol), CuI (3mg), triethylamine (0.41g; 4.08mmol); (9.5mg 0.014mmol) at anhydrous N, reacts in the dinethylformamide with dichloro two (triphenylphosphine) palladium (0); in methyl alcohol, handle then with the NaOH aqueous solution; obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 ' [2-(1-formyl-dimethylamino-4-piperidyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is yellow solid (yield 35mg, 41%)
HRMS (ES
+) m/z is to C
34H
32Cl
2N
4O
4+ H[(M+H)
+] calculated value: 631.1874.Actual measurement: 631.1873.
Embodiment 15a
Preparation intermediate 4-(4-bromo-2-formyl radical-phenoxy group)-piperidines-1-t-butyl formate
M.W.384.27?C
17H
22BrNO
4
With with in the similar mode of method described in the embodiment 4a, make the 5-bromosalicylaldehyde (5.65g, 28mmol) (Aldrich) and 4-(toluene-4-alkylsulfonyl oxygen base)-piperidines-1-t-butyl formate (5g, 14mmol, ASTATECH) and K
2CO
3At N, react in the dinethylformamide, obtain 4-(4-bromo-2-formyl radical-phenoxy group)-piperidines-1-t-butyl formate, be yellow jelly (yield 5.15g, 51%).
Embodiment 15b
Preparation intermediate 1-[5-bromo-2-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.497.51?C
22H
33BrN
2O
4Si
With with in the similar mode of method described in the embodiment 1d; the 4-that will in embodiment 15a, prepare (4-bromo-2-formyl radical-phenoxy group)-piperidines-1-t-butyl formate (5.5g; 14.3mmol) replace 4-(2-formyl radical-4-iodo-phenoxymethyl)-piperidines-1-t-butyl formate as raw material; with 1; 1,3,3; 3-hexamethyldisilazane (3.97mL; 14.3mmol), just-butyllithium (2.5M, 5.7mL; 14.3mmol); trimethylsilyl chloride (1.81mL, 14.3mmol), triethylamine (2.59mL; 18.6mmol) and Acetyl Chloride 98Min. (1.31mL; 18.6mmol) reaction, obtain rough 1-[5-bromo-2-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene; be yellow jelly, and without being used for next step with being further purified.
Embodiment 15c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.715.47?C
34H
34Cl
2BrN
3O
5
With with in the similar mode of method described in the embodiment 1e, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 5b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.8g, 4.62mmol) with 1-[5-bromo-2-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-phenyl of in embodiment 15b, preparing]-3-trimethylsiloxy-2-azepine-1,3-divinyl (14.3mmol) reacts 6h in 140 ℃ in toluene (50mL), obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 4.1g, 15%)
HRMS (ES
+) m/z is to C
34H
34Cl
2BrN
3O
5+ H[(M+H)
+] calculated value: 714.1132.Actual measurement: 714.1134
Embodiment 16a
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.615.36?C
29H
26Cl
2BrN
3O
3
With with in the similar mode of method described in the embodiment 5a, make racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.13g, 0.18mmol) react in methylene dichloride with trifluoroacetic acid, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (yield: 90mg, 82%).
Embodiment 16b
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-bromo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.657.39?C
31H
28Cl
2BrN
3O
4
With with in the similar mode of method described in the embodiment 5a; make racemize (2 ' R; 3R; 4 ' S)-2 '-[5-bromo-2-(4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (90mg; 0.146mmol) (13.8mg 0.175mmol) reacts in anhydrous tetrahydro furan with triethylamine, obtains (2 ' R with Acetyl Chloride 98Min.; 3R; 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-bromo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; be white solid (yield 50mg, 52%).
HRMS (ES
+) m/z is to C
31H
28Cl
2BrN
3O
4+ H[(M+H)
+] calculated value: 656.0713.Actual measurement: 656.0713.
Embodiment 16c
Preparation chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-bromo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.657.39?C
31H
28Cl
2BrN
3O
4
By chirality SFC; from racemize (2 ' R; 3R; 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-bromo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (140mg) separates two enantiomorphs, and chirality (2 ' R, 3R are provided; 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-bromo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (49mg; 35%) (RO5219468-000); and chirality (2 ' S, 3S, 4 ' R)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-bromo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone, for white solid (54mg, 39%) (RO5219469-000).
Embodiment 17a
Preparation intermediate 3-bromo-2-fluoro-6-methoxyl group-phenyl aldehyde
M.W.233.04?C
8H
6BrO
2
To-78 ℃ 4-bromo-3-fluoroanisoles (10g, 48.7mmol, Matrix) in the solution in tetrahydrofuran (THF) (100mL), in 15min, drip lithium diisopropylamine (32.5mL, the THF solution of 1.8M, 58.4mmol).With mixture at-78 ℃ of restir 20mins.Disposable then adding N, and N-dimethyl-methane amide (4.53mL, 58.4mmol).Mixture is stirred 10min at-78 ℃, and (12g, 194mmol) quencher then add entry (61mL) to use acetate then.Mixture is distributed between ethyl acetate and water.Separate organic layer, concentrate.With resistates by chromatography (EtOAc: purifying hexane=1: 4), obtain 3-bromo-2-fluoro-6-methoxyl group-phenyl aldehyde, be yellow solid (yield: 10g, 89%)
Embodiment 17b
Preparation intermediate 3-bromo-2-fluoro-6-hydroxyl-phenyl aldehyde
M.W.219.01?C
7H
4BrFO
2
(9.8g 42.06mmol) in the solution in methylene dichloride (200mL), drips BBr to 3-bromo-2-fluoro-6-methoxyl group-phenyl aldehydes of-50 ℃
3Dichloromethane solution (1M) (126mL, 126mmol).Mixture progressively is warming to room temperature and stirs 1h, water quencher then.With mixture dichloromethane extraction three times.Merge organic layer, use the salt water washing, use MgSO
4Drying concentrates, and obtains 3-bromo-2-fluoro-6-hydroxyl-phenyl aldehyde, is pale solid (yield: 9g, 98%)
Embodiment 17c
Preparation intermediate 4-(4-bromo-3-fluoro-2-formyl radical-phenoxy group)-piperidines-1-t-butyl formate
M.W.402.26?C
17H
21BrFNO
4
With with in the similar mode of method described in the embodiment 4a, make 3-bromo-2-fluoro-6-hydroxyl-phenyl aldehyde (3.69g, 16.8mmol) with 4-(toluene-4-alkylsulfonyl oxygen base)-piperidines-1-t-butyl formate (4g, 11.2mmol, ASTATECH) and K
2CO
3At N, react in the dinethylformamide, obtain 4-(4-bromo-3-fluoro-2-formyl radical-phenoxy group)-piperidines-1-t-butyl formate, be brown oil (yield 4.23g, 94%).
Embodiment 17d
Preparation intermediate 1-[3-bromo-6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-2-fluoro-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.515.50?C
22H
32BrFN
2O
4Si
With with in the similar mode of method described in the embodiment 1d; with 4-(4-bromo-3-fluoro-2-formyl radical-phenoxy group)-piperidines-1-t-butyl formate (4.22g; 10.5mmol) replace 4-(2-formyl radical-4-iodo-phenoxymethyl)-piperidines-1-t-butyl formate as raw material; with 1; 1,3,3; 3-hexamethyldisilazane (2.18mL; 10.5mmol), just-butyllithium (2.5M, 4.2mL; 10.5mmol); trimethylsilyl chloride (1.33mL, 10.5mmol), triethylamine (1.9mL; 13.6mmol) and Acetyl Chloride 98Min. (0.97mL; 13.6mmol) reaction, obtain rough 1-[3-bromo-6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-2-fluoro-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene; be yellow jelly, and without being used for next step with being further purified.
Embodiment 17e
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.733.46?C
34H
33BrCl
2FN
3O
5
With with in the similar mode of method described in the embodiment 1e, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 5b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.36g, 3.5mmol) and 1-[3-bromo-6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-2-fluoro-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (10.5mmol) reacts 6h in 140 ℃ in toluene (30mL), obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be faint yellow solid (yield 0.7g, 28%)
HRMS (ES
+) m/z is to C
34H
33BrCl
2FN
3O
5+ H[(M+H)
+] calculated value: 732.1038.Actual measurement: 732.1035
Embodiment 17f
Preparation chirality (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.733.46?C
34H
33BrCl
2FN
3O
5
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (87mg) separates two enantiomorphs, chirality (2 ' R is provided, 3R, 4 ' S)-2 '-[3-bromo-6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be faint yellow solid (37mg, 43%) (RO5219470-000), and chirality (2 ' S, 3S, 4 ' R)-2 '-[3-bromo-6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for faint yellow solid (28mg, 32%) (RO5219473-000).
Embodiment 18a
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-2-fluoro-6-(4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.633.35?C
29H
25BrCl
2FN
3O
3
With with in the similar mode of method described in the embodiment 5a, make racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.6g, 0.818mmol) react in methylene dichloride with trifluoroacetic acid, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-2-fluoro-6-(4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is yellow solid (yield: 0.5g, 98%).
Embodiment 18b
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[6-(1-ethanoyl-4-piperidyl oxygen base)-3-bromo-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.675.38?C
31H
27BrCl
2FN
3O
4
With with in the similar mode of method described in the embodiment 5a; make racemize (2 ' R; 3R; 4 ' S)-2 '-[3-bromo-2-fluoro-6-(4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (0.1g; 0.158mmol) (14.9mg 0.189mmol) reacts in anhydrous tetrahydro furan with triethylamine, obtains racemize (2 ' R with Acetyl Chloride 98Min.; 3R; 4 ' S)-2 '-[6-(1-ethanoyl-4-piperidyl oxygen base)-3-bromo-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; be pale solid (yield 48mg, 45%).
HRMS (ES
+) m/z is to C
31H
27BrCl
2FN
3O
4+ H[(M+H)
+] calculated value: 674.0619.Actual measurement: 674.0617.
Embodiment 19a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-ethyl-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.690.41?C
31H
30Cl
2IN
3O
3
With with in the similar mode of method described in the embodiment 7, make the racemize (2 ' R that in embodiment 5a, prepares, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.17g, 0.257mmol) with acetaldehyde (22mg, 0.514mmol) and NaCNBH
3(22.5mg, 0.39mmol) in methyl alcohol, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-ethyl-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be pale solid (yield 80mg, 45%).
Embodiment 19b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-ethyl-4-piperidyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.588.53?C
33H
31Cl
2N
3O
3
With with in the similar mode of method described in the embodiment 6a, make racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-ethyl-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (80mg, 0.116mmol) and trimethyl silyl acetylene (0.114g, 1.16mmol), CuI (5mg), triethylamine (0.35g, 3.46mmol), (8mg 0.012mmol) at anhydrous N, reacts in the dinethylformamide with dichloro two (triphenylphosphine) palladium (0), in methyl alcohol, handle then with the NaOH aqueous solution, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-ethynyl-4-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is pale solid (yield 54mg, 79%)
HRMS (ES
+) m/z is to C
33H
31Cl
2N
3O
3+ H[(M+H)
+] calculated value: 588.1815.Actual measurement: 588.1818.
Embodiment 20a
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-2-fluoro-6-(1-methyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.647.37?C
30H
27BrCl
2FN
3O
3
With with in the similar mode of method described in the embodiment 7, make the racemize (2 ' R that in embodiment 18a, prepares, 3R, 4 ' S)-2 '-[3-bromo-2-fluoro-6-(4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.12g, 0.189mmol) and formaldehyde (37wt%, Aldrich, 0.028mL, 0.38mmol) and NaCNBH
3(18mg, 0.28mmol) in methyl alcohol, react, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-2-fluoro-6-(1-methyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-diindyl-3,3 '-piperidines]-2,6 ' (1H)-diketone, be pale solid (yield 25mg, 20%).
HRMS (ES
+) m/z is to C
30H
27BrCl
2FN
3O
3+ H[(M+H)
+] calculated value: 646.0670.Actual measurement: 646.0674.
Embodiment 20b
Preparation chirality (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-2-fluoro-6-(1-methyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.647.37?C
30H
27BrCl
2FN
3O
3
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-2-fluoro-6-(1-methyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (105mg) separates two enantiomorphs, chirality (2 ' R is provided, 3R, 4 ' S)-2 '-[3-bromo-2-fluoro-6-(1-methyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be pale solid (39mg, 37%) (RO5221404-000), and chirality (2 ' S, 3S, 4 ' R)-2 '-[3-bromo-2-fluoro-6-(1-methyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for faint yellow solid (41mg, 39%) (RO5221405-000).
Embodiment 21a
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-formyl-dimethylamino-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.704.42?C
32H
30BrCl
2FN
4O
4
With with in the similar mode of method described in the embodiment 5b; make the racemize (2 ' R that in embodiment 18a, prepares; 3R; 4 ' S)-2 '-[3-bromo-2-fluoro-6-(4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (42mg; 0.066mmol) and dimethylcarbamyl chloride (8.54mg; 0.079mmol) and Trimethylamine in tetrahydrofuran (THF), react; obtain racemize (2 ' R; 3R; 4 ' S)-2 '-[3-bromo-6-(1-formyl-dimethylamino-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; be pale solid (yield 27mg, 58%).
HRMS (ES
+) m/z is to C
32H
30BrCl
2FN
4O
4+ H[(M+H)
+] calculated value: 703.0885.Actual measurement: 703.0882.
Embodiment 21b
Preparation chirality (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-formyl-dimethylamino-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.704.42?C
32H
303rCl
2FN
4O
4
By chirality SFC; from racemize (2 ' R; 3R; 4 ' S)-2 '-[3-bromo-6-(1-formyl-dimethylamino-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (100mg) separates two enantiomorphs; chirality (2 ' R is provided; 3R; 4 ' S)-2 '-[3-bromo-6-(1-formyl-dimethylamino-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be pale solid (28mg; 28%) (RO5219463-000); and chirality (2 ' S, 3S, 4 ' R)-2 '-[3-bromo-6-(1-formyl-dimethylamino-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone, for faint yellow solid (23mg, 23%) (RO5219466-000).
Embodiment 22a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-diethylamino formyl radical-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.761.49?C
34H
35Cl
2IN
4O
4
With with in the similar mode of method described in the embodiment 5b; with diethylamino formyl chloride (24.6mg; 0.18mmol) replacing acetyl chloride is as raw material; with the racemize that in embodiment 5a, prepares (2 ' R; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (0.1g; 0.15mmol) and triethylamine in tetrahydrofuran (THF), react; obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-diethylamino formyl radical-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 50mg, 36%).
Embodiment 22b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-diethylamino formyl radical-4-piperidyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.659.61?C
36H
36Cl
2N
4O
4
With with in the similar mode of method described in the embodiment 6a; make racemize (2 ' R; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-diethylamino formyl radical-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (50mg; 0.066mmol) and trimethyl silyl acetylene (64.7mg; 0.66mmol), CuI (5mg), triethylamine (0.2g; 1.97mmol); (4.56mg 0.0066mmol) at anhydrous N, reacts in the dinethylformamide with dichloro two (triphenylphosphine) palladium (0); in methyl alcohol, handle then with the NaOH aqueous solution; obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-diethylamino formyl radical-4-piperidyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is yellow solid (yield 36mg, 83%)
HRMS (ES
+) m/z is to C
36H
36Cl
2N
4O
4+ H[(M+H)
+] calculated value: 659.2187.Actual measurement: 659.2192.
Embodiment 23a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-iodo-2-[1-(tetramethyleneimine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.759.48?C
34H
33Cl
2IN
4O
4
With with in the similar mode of method described in the embodiment 5b, with 1-pyrrolidine formyl chlorine (24.2mg, 0.18mmol) replacing acetyl chloride is as raw material, with the racemize that in embodiment 5a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.1g, 0.15mmol) and triethylamine in tetrahydrofuran (THF), react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-{ 5-iodo-2-[1-(tetramethyleneimine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (yield 90mg, 82%).
HRMS (ES
+) m/z is to C
34H
33Cl
2IN
4O
4+ H[(M+H)
+] calculated value: 759.0997.Actual measurement: 759.1002.
Embodiment 23b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[1-(tetramethyleneimine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.657.60?C
36H
34Cl
2N
4O
4
With with in the similar mode of method described in the embodiment 6a, make racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-iodo-2-[1-(tetramethyleneimine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (90mg, 0.118mmol) and trimethyl silyl acetylene (0.117g, 1.18mmol), CuI (5mg), triethylamine (0.36g, 3.55mmol), (8.3mg 0.012mmol) at anhydrous N, reacts in the dinethylformamide with dichloro two (triphenylphosphine) palladium (0), in methyl alcohol, handle then with the NaOH aqueous solution, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-{ 5-ethynyl-2-[1-(tetramethyleneimine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white white solid (yield 8mg, 10%)
HRMS (ES
+) m/z is to C
36H
34Cl
2N
4O
4+ H[(M+H)
+] calculated value: 657.2030.Actual measurement: 657.2034.
Embodiment 24a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-sec.-propyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.704.44?C
32H
32Cl
2IN
3O
3
To the racemize that in embodiment 5a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines] (0.1g is 0.15mmol) at N for-2,6 ' (1H)-diketone, in the solution in the dinethylformamide (2mL), add triethylamine (30.5mg, 0.3mmol) and 2-iodopropane (77mg, 0.45mmol).Reaction mixture is heated 24h at 75 ℃.With the mixture cool to room temperature,, wash with water with the ethyl acetate dilution.Separate organic layer, and with the water layer ethyl acetate extraction.Merge organic layer, use the salt water washing, use MgSO
4Drying concentrates, and obtains rough racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-sec.-propyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is faint yellow solid (yield 80mg, 73%).
Embodiment 24b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-sec.-propyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.602.56?C
34H
33Cl
2N
3O
3
With with in the similar mode of method described in the embodiment 6a, make racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-sec.-propyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (80mg, 0.11mmol) and trimethyl silyl acetylene (0.11g, 1.1mmol), CuI (5mg), triethylamine (0.34g, 3.3mmol), (8mg 0.012mmol) at anhydrous N, reacts in the dinethylformamide with dichloro two (triphenylphosphine) palladium (0), in methyl alcohol, handle then with the NaOH aqueous solution, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-sec.-propyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is pale solid (yield 10mg, 15%)
HRMS (ES
+) m/z is to C
34H
33Cl
2N
3O
3+ H[(M+H)
+] calculated value: 602.1972.Actual measurement: 602.1977.
Embodiment 25a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-iodo-2-[1-(2-oxo-imidazolidine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.774.45?C
33H
30Cl
2IN
5O
5
With with in the similar mode of method described in the embodiment 5b, with 1-chloroformyl-2-imidazolidone (40.4mg, 0.27mmol) (Aldrich) replacing acetyl chloride is as raw material, with the racemize that in embodiment 5a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.15g, 0.23mmol) and triethylamine in tetrahydrofuran (THF), react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-{ 5-iodo-2-[1-(2-oxo-imidazolidine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (yield 0.12g, 71%).
Embodiment 25b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[1-(2-oxo-imidazolidine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.672.57?C
35H
31Cl
2N
5O
5
With with in the similar mode of method described in the embodiment 6a, make racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-iodo-2-[1-(2-oxo-imidazolidine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.12g, 0.15mmol) and trimethyl silyl acetylene (0.15g, 1.55mmol), CuI (5mg), triethylamine (0.47g, 4.65mmol), (11mg 0.016mmol) at anhydrous N, reacts in the dinethylformamide with dichloro two (triphenylphosphine) palladium (0), in methyl alcohol, handle then with the NaOH aqueous solution, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-{ 5-ethynyl-2-[1-(2-oxo-imidazolidine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is pale solid (yield 25mg, 25%)
HRMS (ES
+) m/z is to C
35H
31Cl
2N
5O
5+ H[(M+H)
+] calculated value: 672.1775.Actual measurement: 672.1774.
Embodiment 26a
Preparation intermediate 3-chloro-2-fluoro-6-methoxyl group-phenyl aldehyde
M.W.188.59?C
8H
6ClO
2
To-78 ℃ 4-chloro-3-fluoroanisoles (10.2g, 63.5mmol, Oakwood) in the solution in tetrahydrofuran (THF) (100mL), in 15min, drip lithium diisopropylamine (42.3mL, the THF solution of 1.8M, 76.2mmol).With mixture at-78 ℃ of restir 20mins.Disposable then adding N, and N-dimethyl-methane amide (5.9mL, 76.2mmol).Mixture is stirred 10min at-78 ℃, and (15.6g, 254mmol) quencher then add entry (80mL) to use acetate then.Mixture is distributed between ethyl acetate and water.Separate organic layer, concentrate, obtain 3-chloro-2-fluoro-6-methoxyl group-phenyl aldehyde, be yellow solid (yield: 10g, 85%)
Embodiment 25b
Preparation intermediate 3-chloro-2-fluoro-6-hydroxyl-phenyl aldehyde
M.W.174.56?C
7H
4ClFO
2
(10g 53.2mmol) in the solution in methylene dichloride (200mL), drips BBr to 3-chloro-2-fluoro-6-methoxyl group-phenyl aldehydes of-78 ℃
3Dichloromethane solution (1M) (159mL, 159mmol).Mixture progressively is warming to room temperature and stirs 1h, water quencher then.With mixture dichloromethane extraction three times.Merge organic layer, use the salt water washing, use MgSO
4Drying concentrates, and obtains resistates.Resistates is ground with methylene dichloride and hexane, obtain 3-chloro-2-fluoro-6-hydroxyl-phenyl aldehyde, be brown solid (yield: 2.07g, 22%)
Embodiment 25c
Preparation intermediate 4-(4-chloro-3-fluoro-2-formyl radical-phenoxy group)-piperidines-1-t-butyl formate
M.W.357.81?C
17H
21ClFNO
4
With with in the similar mode of method described in the embodiment 4a, make 3-chloro-2-fluoro-6-hydroxyl-phenyl aldehyde (2.07g, 11.8mmol) with 4-(toluene-4-alkylsulfonyl oxygen base)-piperidines-1-t-butyl formate (3.51g, 9.88mmol, ASTATECH) and K
2CO
3At N, react in the dinethylformamide, obtain 4-(4-chloro-3-fluoro-2-formyl radical-phenoxy group)-piperidines-1-t-butyl formate, be brown oil (yield 3.75g, 84%).
Embodiment 25d
Preparation intermediate 1-[6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-3-chloro-2-fluoro-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.471.05?C
22H
32ClFN
2O
4Si
With with in the similar mode of method described in the embodiment 1d; with 4-(4-chloro-3-fluoro-2-formyl radical-phenoxy group)-piperidines-1-t-butyl formate (3.75g; 10.5mmol) replace 4-(2-formyl radical-4-iodo-phenoxymethyl)-piperidines-1-t-butyl formate as raw material; with 1; 1,3,3; 3-hexamethyldisilazane (2.18mL; 10.5mmol), just-butyllithium (2.5M, 4.2mL; 10.5mmol); trimethylsilyl chloride (1.33mL, 10.5mmol), triethylamine (1.9mL; 13.6mmol) and Acetyl Chloride 98Min. (0.97mL; 13.6mmol) reaction, obtain rough 1-[6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-3-chloro-2-fluoro-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene; be yellow jelly, and without being used for next step with being further purified.
Embodiment 25e
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-3-chloro-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.689.01?C
34H
33Cl
3FN
3O
5
With with in the similar mode of method described in the embodiment 1e, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 5b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.63g, 4.2mmol) and 1-[6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-3-chloro-2-fluoro-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (10.5mmol) reacts 6h in 140 ℃ in toluene (50mL), obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-3-chloro-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be faint yellow solid (yield 1.13g, 39%)
HRMS (ES
+) m/z is to C
34H
33Cl
3FN
3O
5+ H[(M+H)
+] calculated value: 688.1543.Actual measurement: 688.1541.
Embodiment 26a
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[3-chloro-2-fluoro-6-(4-piperidyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.588.90?C
29H
25Cl
3FN
3O
3
With with in the similar mode of method described in the embodiment 5a, make racemize (2 ' R, 3R, 4 ' S)-2 '-[6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-3-chloro-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (1.0g, 1.45mmol) react in methylene dichloride with trifluoroacetic acid, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[3-chloro-2-fluoro-6-(4-piperidyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is yellow solid (yield: 0.85g, 100%).
Embodiment 26b
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[6-(1-ethanoyl-4-piperidyl oxygen base)-3-chloro-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.630.93C
31H
27Cl
3FN
3O
4
With with in the similar mode of method described in the embodiment 5a; make racemize (2 ' R; 3R; 4 ' S)-6-chloro-2 '-[3-chloro-2-fluoro-6-(4-piperidyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (72.5mg; 0.123mmol) (11.6mg 0.148mmol) reacts in anhydrous tetrahydro furan with triethylamine, obtains racemize (2 ' R with Acetyl Chloride 98Min.; 3R; 4 ' S)-2 '-[6-(1-ethanoyl-4-piperidyl oxygen base)-3-chloro-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; be pale solid (yield 30mg, 39%).
HRMS (ES
+) m/z is to C
31H
27Cl
3FN
3O
4The calculated value of+H [(M+H)
+]: 630.1124.Actual measurement: 630.1128.
Embodiment 27
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[3-chloro-6-(1-formyl-dimethylamino-4-piperidyl oxygen base)-2-fluoro-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.659.97?C
32H
30Cl
3FN
4O
4
With with in the similar mode of method described in the embodiment 5b; make the racemize (2 ' R that in embodiment 26a, prepares; 3R; 4 ' S)-6-chloro-2 '-[3-chloro-2-fluoro-6-(4-piperidyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (87.7mg; 0.149mmol) and dimethylcarbamyl chloride (19.2mg; 0.178mmol) and Trimethylamine in tetrahydrofuran (THF), react; obtain racemize (2 ' R; 3R; 4 ' S)-6-chloro-2 '-[3-chloro-6-(1-formyl-dimethylamino-4-piperidyl oxygen base)-2-fluoro-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; be pale solid (yield 51mg, 52%).
HRMS (ES
+) m/z is to C
32H
30Cl
3FN
4O
4+ H[(M+H)
+] calculated value: 659.1390.Actual measurement: 659.1392.
Embodiment 28
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[3-chloro-6-(1-methylamino formyl radical-4-piperidyl oxygen base)-2-fluoro-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.645.94?C
32H
28Cl
3FN
4O
4
To the racemize that in embodiment 26a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[3-chloro-2-fluoro-6-(4-piperidyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2, (0.1g 0.17mmol) in the solution in methylene dichloride (2mL), adds triethylamine (34.3mg to 6 ' (1H)-diketone, 0.34mmol) and methyl isocyanate (11.6mg, 0.2mmol).With reaction mixture at stirring at room 0.5h.Mixture is diluted with methylene dichloride, and MgSO is used in water and salt water washing
4Drying is filtered and is concentrated.Resistates is ground with methylene dichloride and hexane; obtain racemize (2 ' R; 3R; 4 ' S)-6-chloro-2 '-[3-chloro-6-(1-methylamino formyl radical-4-piperidyl oxygen base)-2-fluoro-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is faint yellow solid (yield 23mg, 21%).
HRMS (ES
+) m/z is to C
32H
28Cl
3FN
4O
4+ H[(M+H)
+] calculated value: 645.1233.Actual measurement: 645.1232.
Embodiment 29
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-methylamino formyl radical-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.690.39?C
32H
28BrCl
2FN
4O
4
With with in the similar mode of method described in the embodiment 28; make the racemize (2 ' R that in embodiment 18a, prepares; 3R; 4 ' S)-2 '-[3-bromo-2-fluoro-6-(4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (40mg; 0.063mmol) and triethylamine and methyl isocyanate (4.3mg; 0.076mmol) reaction; obtain racemize (2 ' R; 3R; 4 ' S)-2 '-[3-bromo-6-(1-methylamino formyl radical-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; be faint yellow solid (yield 37mg, 85%).
HRMS (ES
+) m/z is to C
32H
28BrCl
2FN
4O
4+ H[(M+H)
+] calculated value: 689.0728.Actual measurement: 689.0732.
Embodiment 30
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-formyl-dimethylamino-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.733.43C
32H
31Cl
2IN
4O
4
With with in the similar mode of method described in the embodiment 5b; make the racemize (2 ' R that in embodiment 5a, prepares; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (0.1g; 0.15mmol) and dimethylcarbamyl chloride (19.5mg; 0.18mmol) and Trimethylamine in tetrahydrofuran (THF), react; obtain racemize (2 ' R; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-formyl-dimethylamino-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; be pale solid (yield 75mg, 68%).
HRMS (ES
+) m/z is to C
32H
31Cl
2IN
4O
4+ H[(M+H)
+] calculated value: 733.0840.Actual measurement: 733.0841.
Embodiment 31a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-iodo-2-[1-(4-methylpiperazine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.788.52C
35H
36Cl
2IN
5O
4
With with in the similar mode of method described in the embodiment 5b, make the racemize (2 ' R that in embodiment 5a, prepares, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.15g, 0.23mmol) and 4-methylpiperazine-1-formyl chloride (44.5mg, 0.27mmol) and Trimethylamine in tetrahydrofuran (THF), react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-iodo-2-[1-(4-methylpiperazine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be yellow jelly (yield 0.19g, 99%).
Embodiment 31b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[1-(4-methylpiperazine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.686.64?C
37H
37Cl
2N
5O
4
With with in the similar mode of method described in the embodiment 6a, make racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-iodo-2-[1-(4-methylpiperazine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.18g, 0.23mmol) and trimethyl silyl acetylene (0.23g, 2.28mmol), CuI (5mg), triethylamine (0.69g, 6.8mmol), (16mg 0.023mmol) at anhydrous N, reacts in the dinethylformamide with dichloro two (triphenylphosphine) palladium (0), in methyl alcohol, handle then with the NaOH aqueous solution, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-{ 5-ethynyl-2-[1-(4-methylpiperazine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is brown solid (yield 0.12g, 71%)
HRMS (ES
+) m/z is to C
37H
37Cl
2N
5O
4+ H[(M+H)
+] calculated value: 686.2296.Actual measurement: 686.2295.
Embodiment 32a
Preparation intermediate methylsulfonic acid tetrahydropyran-4-base ester
M.W.180.22?C
6H
12O
4S
To 0 ℃ 4-hydroxy tetrahydro pyrans (4.5g, 44mmol) in (Aldrich) solution in methylene dichloride (90mL), add triethylamine (5.4g, 53mmol) and methylsulfonyl chloride (3.73mL, 48mmol, Aldrich).Reaction mixture is stirred 1h at 0 ℃, then at stirring at room 1.5h.Mixture is poured in the water, used dichloromethane extraction.Separate organic layer, MgSO is used in water, salt water washing
4Drying and concentrated obtains rough methylsulfonic acid tetrahydropyran-4-base ester, is white solid (yield 8g, 100%).
Similarly change by Suto, M.J. etc. are at J.Med.Chem, describe in 1991,2484.
Embodiment 32b
Preparation intermediate 5-iodo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl aldehyde
M.W.332.14?C
12H
13IO
3
With with in the similar mode of method described in the embodiment 4a, make 5-iodine salicylic aldehyde (3g, 12.1mmol) (Aldrich) and methylsulfonic acid tetrahydropyran-4-base ester (4g, 22mmol) and K
2CO
3At N, react in the dinethylformamide, obtain 5-iodo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl aldehyde, be yellow solid (yield 3.4g, 85%).
Embodiment 32c
Preparation intermediate 1-[5-iodo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.445.38?C
17H
24INO
3Si
With with in the similar mode of method described in the embodiment 1d; with 5-iodo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl aldehyde (3.3g; 10mmol) replace 4-(2-formyl radical-4-iodo-phenoxymethyl)-piperidines-1-t-butyl formate as raw material; with 1; 1,3,3; 3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL; 10mmol); trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.36g; 13.6mmol) and Acetyl Chloride 98Min. (1g; 13.6mmol) reaction, obtain rough 1-[5-iodo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene; be yellow jelly, and without being used for next step with being further purified.
Embodiment 32d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.663.33?C
29H
25Cl
2IN
2O
4
The E/Z-6-chloro-3-that will in embodiment 5b, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-t-butyl formate (1.2g, 3mmol) join 1-[5-iodo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-the 3-trimethylsiloxy-solution of 2-azepine-1,3-butadiene (10mmol) in toluene (30mL) in.Reaction mixture is heated 2h in 140 ℃ under nitrogen.With the mixture cool to room temperature, concentrate.Resistates with methylene dichloride (10mL) dilution, is then added trifluoroacetic acid (5mL).Reaction mixture at stirring at room 1h, is concentrated then.With resistates NaHCO
3The aqueous solution is neutralized to " pH " 7.Then with the mixture ethyl acetate extraction.Separate organic layer, use the salt water washing, use MgSO
4Drying and concentrated.Resistates is passed through chromatography (EtOAc: CH
2Cl
2=1: 1) purifying obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be yellow solid (yield 1.5g, 75%)
HRMS (ES
+) m/z is to C
29H
25Cl
2IN
2O
4+ H[(M+H)
+] calculated value: 663.0309.Actual measurement: 663.0309.
Embodiment 33a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.561.46?C
31H
26Cl
2N
2O
4
With with in the similar mode of method described in the embodiment 2, make racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines] (1.3g is 1.97mmol) with trimethyl silyl acetylene (0.4g for-2,6 ' (1H)-diketone, 3.94mmol), CuI (0.75g, 3.94mmol), triethylamine (0.4mL, 3.94mmol) and dichloro two (triphenylphosphine) palladium (0) (0.28g, 0.39mmol) reaction, in methyl alcohol, handle then with the NaOH aqueous solution, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be pale solid (yield 0.62g, 56%).
HRMS (ES
+) m/z is to C
31H
26Cl
2N
2O
4+ H[(M+H)
+] calculated value: 561.1343.Actual measurement: 561.1342.
Embodiment 33b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.561.46?C
31H
26Cl
2N
2O
4
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.6g) separates two enantiomorphs, and chirality (2 ' R, 3R are provided, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be pale solid (0.177g, 30%) (RO5236850-000), and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for pale solid (0.176g, 29%) (RO5236849-000).
Embodiment 34a
Preparation intermediate 5-bromo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl aldehyde
M.W.285.14?C
12H
13BrO
3
With with in the similar mode of method described in the embodiment 4a, make the 5-bromosalicylaldehyde (3g, 15mmol) (Aldrich) and the methylsulfonic acid tetrahydropyran-4-base ester that in embodiment 32a, prepares (4g, 22mmol) and K
2CO
3At N, react in the dinethylformamide, obtain 5-bromo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl aldehyde, be yellow solid (yield 2.86g, 67%).
Embodiment 34b
Preparation intermediate 1-[5-bromo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.398.38?C
17H
24BrNO
3Si
With with in the similar mode of method described in the embodiment 1d; with 5-bromo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl aldehyde (2.86g; 10mmol) replace 4-(2-formyl radical-4-iodo-phenoxymethyl)-piperidines-1-t-butyl formate as raw material; with 1; 1,3,3; 3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL; 10mmol); trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.36g; 13.6mmol) and Acetyl Chloride 98Min. (1g; 13.6mmol) reaction, obtain rough 1-[5-iodo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene; be yellow jelly, and without being used for next step with being further purified.
Embodiment 34c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.616.34?C
29H
25BrCl
2N
2O
4
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 5b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.0g, 2.5mmol) and 1-[5-bromo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (4g, 10mmol) in toluene in 140 ℃ of reactions, handle in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is yellow solid (yield 0.76g, 49%)
HRMS (ES
+) m/z is to C
29H
25BrCl
2N
2O
4+ H[(M+H)
+] calculated value: 615.0448.Actual measurement: 615.0444.
Embodiment 34d
Preparation chirality (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.616.34?C
29H
25BrCl
2N
2O
4
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.7g) separates two enantiomorphs, and chirality (2 ' R, 3R are provided, 4 ' S)-2 '-[5-bromo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be yellow solid (0.208g, 30%) (RO5249032-000), and chirality (2 ' S, 3S, 4 ' R)-2 '-[5-bromo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for yellow solid (0.21g, 30%) (RO5249031-000).
Embodiment 35a
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[1-(1-tetramethyleneimine-carbonyl)-4-piperidyl oxygen base]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.712.47?C
34H
33BrCl
2N
4O
4
With with in the similar mode of method described in the embodiment 5b, with 1-pyrrolidine formyl chlorine (26mg, 0.195mmol) replacing acetyl chloride is as raw material, with the racemize that in embodiment 16a, prepares (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.1g, 0.16mmol) and triethylamine in tetrahydrofuran (THF), react, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-{ 5-bromo-2-[1-(1-tetramethyleneimine-carbonyl)-4-piperidyl oxygen base]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is yellow solid (yield 54mg, 82%).
HRMS (ES
+) m/z is to C
34H
33BrCl
2N
4O
4+ H[(M+H)
+] calculated value: 711.1135.Actual measurement: 711.1133.
Embodiment 35b
Preparation chirality (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[1-(1-tetramethyleneimine-carbonyl)-4-piperidyl oxygen base]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.712.47C
34H
33BrCl
2N
4O
4
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[1-(1-tetramethyleneimine-carbonyl)-4-piperidyl oxygen base]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (140mg) separates two enantiomorphs, chirality (2 ' R is provided, 3R, 4 ' S)-2 '-5-bromo-2-[1-(1-tetramethyleneimine-carbonyl)-4-piperidyl oxygen base]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be faint yellow solid (38mg, 27%) (RO5221431-000), and chirality (2 ' S, 3S, 4 ' R)-2 '-5-bromo-2-[1-(1-tetramethyleneimine-carbonyl)-4-piperidyl oxygen base]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for faint yellow solid (37mg, 26%) (RO5221430-000).
Embodiment 36
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-formyl-dimethylamino-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.686.43?C
32H
31BrCl
2N
4O
4
With with in the similar mode of method described in the embodiment 5b; with dimethylcarbamyl chloride (25mg; 0.234mmol) replacing acetyl chloride is as raw material; with the racemize that in embodiment 16a, prepares (2 ' R; 3R; 4 ' S)-2 '-[5-bromo-2-(4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (0.12g; 0.195mmol) and triethylamine in tetrahydrofuran (THF), react; obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-formyl-dimethylamino-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is faint yellow solid (yield 87mg, 65%).
HRMS (ES
+) m/z is to C
32H
31BrCl
2N
4O
4+ H[(M+H)
+] calculated value: 685.0979.Actual measurement: 685.0975.
Embodiment 37
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-ethoxy carbonyl-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.734.41?C
32H
30Cl
2IN
3O
5
With with in the similar mode of method described in the embodiment 5b, make the racemize (2 ' R that in embodiment 5a, prepares, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.15g, 0.23mmol) and Vinyl chloroformate (29.4mg, 0.27mmol) and Trimethylamine in tetrahydrofuran (THF), react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-ethoxy carbonyl-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be faint yellow solid (yield 0.11g, 65%).
HRMS (ES
+) m/z is to C
32H
30Cl
2IN
3O
5+ H[(M+H)
+] calculated value: 734.0680.Actual measurement: 734.0682.
Embodiment 38
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-ethoxy carbonyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.687.42?C
32H
30BrCl
2N
3O
5
With with in the similar mode of method described in the embodiment 5b, make the racemize (2 ' R that in embodiment 16a, prepares, 3R, 4 ' S)-2 '-[5-bromo-2-(4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.11g, 0.179mmol) and Vinyl chloroformate (23.3mg, 0.214mmol) and triethylamine in tetrahydrofuran (THF), react, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-ethoxy carbonyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 17mg, 14%).
HRMS (ES
+) m/z is to C
32H
30BrCl
2N
3O
5+ H[(M+H)
+] calculated value: 686.0819.Actual measurement: 686.0814.
Embodiment 39
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-isobutyryl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.685.44?C
33H
32BrCl
2N
3O
4
With with in the similar mode of method described in the embodiment 5b; make the racemize (2 ' R that in embodiment 16a, prepares; 3R; 4 ' S)-2 '-[5-bromo-2-(4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (50mg; 0.081mmol) (10mg 0.097mmol) reacts in tetrahydrofuran (THF) with triethylamine, obtains racemize (2 ' R with isobutyryl chloride; 3R; 4 ' S)-2 '-[5-bromo-2-(1-isobutyryl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; be faint yellow solid (yield 42mg, 76%).
HRMS (ES
+) m/z is to C
33H
32BrCl
2N
3O
4+ H[(M+H)
+] calculated value: 684.1026.Actual measurement: 684.1025.
Embodiment 40
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-isopropoxy carbonyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.701.44?C
33H
32BrCl
2N
3O
5
With with in the similar mode of method described in the embodiment 5b, make the racemize (2 ' R that in embodiment 16a, prepares, 3R, 4 ' S)-2 '-[5-bromo-2-(4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.1g, 0.16mmol) and isopropyl chlorocarbonate (0.19mL, 0.196mmol) and triethylamine in tetrahydrofuran (THF), react, obtain racemize (2, R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-isopropoxy carbonyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (yield 27mg, 24%).
HRMS (ES
+) m/z is to C
33H
32BrCl
2N
3O
5+ H[(M+H)
+] calculated value: 700.0975.Actual measurement: 700.0972.
Embodiment 41
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-isobutyryl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.732.44C
33H
32Cl
2IN
3O
4
With with in the similar mode of method described in the embodiment 5b; make the racemize (2 ' R that in embodiment 5a, prepares; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (0.15g; 0.23mmol) (29mg 0.27mmol) reacts in tetrahydrofuran (THF) with Trimethylamine, obtains racemize (2 ' R with isobutyryl chloride; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-isobutyryl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; be faint yellow solid (yield 91mg, 54%).
HRMS (ES
+) m/z is to C
33H
32Cl
2IN
3O
4+ H[(M+H)
+] calculated value: 732.0888.Actual measurement: 732.0892.
Embodiment 42
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-isopropoxy carbonyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.748.44C
33H
32Cl
2IN
3O
5
With with in the similar mode of method described in the embodiment 5b, make the racemize (2 ' R that in embodiment 5a, prepares, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.1g, 0.15mmol) and isopropyl chlorocarbonate (0.15mL, 0.15mmol) and Trimethylamine in tetrahydrofuran (THF), react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-isopropoxy carbonyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be faint yellow solid (yield 54mg, 48%).
HRMS (ES
+) m/z is to C
33H
32Cl
2IN
3O
5+ H[(M+H)
+] calculated value: 748.0837.Actual measurement: 748.0835.
Embodiment 43
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2-[1-(2-hydroxyl-ethyl)-4-piperidyl oxygen base]-5-iodo-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.706.40?C
31H
30Cl
2IN
3O
4
To the racemize that in embodiment 5a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2, (0.1g 0.15mmol) in the solution in ethanol (2mL), adds triethylamine (45.7mg to 6 ' (1H)-diketone, 0.46mmol) and ethylene bromohyrin (42.4mg, 0.345mmol) (Aldrich).At 80 ℃ of heating 18h, cool to room temperature is with concentrated then with reaction mixture.Resistates is distributed between ethyl acetate and water.Separate organic layer, and with the water layer ethyl acetate extraction.Merge organic layer, use the salt water washing, MgSO
4Drying and concentrated.Resistates is passed through chromatography (MeOH: EtOAc: NEt
3=12: 88: 5) purifying obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2-[1-(2-hydroxyl-ethyl)-4-piperidyl oxygen base]-5-iodo-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 36mg, 34%)
HRMS (ES
+) m/z is to C
31H
30Cl
2IN
3O
4+ H[(M+H)
+] calculated value: 706.0731.Actual measurement: 706.0729.
Embodiment 44
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-methoxycarbonyl methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.734.41C
32H
30Cl
2IN
3O
5
To the racemize that in embodiment 5a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2, (0.36g 0.54mmol) in the solution in ethanol (2mL), adds triethylamine (0.15mL to 6 ' (1H)-diketone, 1.08mmol) and methyl bromoacetate (0.124g, 0.81mmol) (Aldrich).Reaction mixture is heated 2h, cool to room temperature then at 80 ℃.Mixture is distributed between methylene dichloride and water.Separate organic layer, and with the water layer dichloromethane extraction.Merge organic layer, use the salt water washing, MgSO
4Drying and concentrated.Resistates is passed through chromatography (MeOH: EtOAc=7: 93) purifying, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-methoxycarbonyl methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is faint yellow solid (yield 0.21g, 53%)
HRMS (ES
+) m/z is to C
32H
30Cl
2IN
3O
5+ H[(M+H)
+] calculated value: 734.0680.Actual measurement: 734.0683.
Embodiment 45
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-tertiary butyloxycarbonyl ylmethyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.776.49C
35H
36Cl
2IN
3O
5
With with in the similar mode of method described in the embodiment 44, racemize (2 ' the R that will in embodiment 5a, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.32g, 0.48mmol) and bromo-acetic acid tert-butyl (0.14g, 0.72mmol) and triethylamine in ethanol, react, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-tertiary butyloxycarbonyl ylmethyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be faint yellow solid (yield 0.25g, 67%)
HRMS (ES
+) m/z is to C
35H
36Cl
2IN
3O
5+ H[(M+H)
+] calculated value: 776.1150.Actual measurement: 776.1147.
Embodiment 46
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-hydroxycarbonyl group methyl-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.720.38?C
31H
28Cl
2IN
3O
5
To racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-tertiary butyloxycarbonyl ylmethyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.22g, 0.28mmol) in the solution in methylene dichloride (2mL), add trifluoroacetic acid (2mL).Reaction mixture at stirring at room 18h, is concentrated then.Resistates is ground with methylene dichloride and hexane, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-hydroxycarbonyl group methyl 4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is trifluoroacetate: yellow solid (yield 0.18g)
HRMS (ES
+) m/z is to C
31H
28Cl
2IN
3O
5+ H[(M+H)
+] calculated value: 720.0524.Actual measurement: 720.0525.
Embodiment 47a
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-carbamyl ylmethyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.719.40?C
31H
29Cl
2IN
4O
4
To racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-hydroxycarbonyl group methyl-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines] (50mg is 0.069mmol) at anhydrous N for-2,6 ' (1H)-diketone, in the solution in the dinethylformamide (2mL), adding EDCI (26.5mg, 0.139mmol), HOBT (18.8mg, 0.139mmol), diisopropyl ethyl amine (35.9mg, 0.278mmol), NH
4Cl (7.4mg, 0.278mmol).Reaction mixture is heated 1h, cool to room temperature then at 80 ℃.Mixture is distributed between ethyl acetate and water.Separate organic layer, and use the ethyl acetate extraction water layer.Merge organic layer, use the salt water washing, use MgSO
4Drying and concentrated.Resistates is passed through chromatography (MeOH: EtOAc=8: 92) purifying; obtain racemize (2 ' R; 3R; 4 ' S)-2 '-[2-(1-carbamyl ylmethyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (yield 25.6mg, 51%)
HRMS (ES
+) m/z is to C
31H
29Cl
2IN
4O
4+ H[(M+H)
+] calculated value: 719.0684.Actual measurement: 719.0690.
Embodiment 47b
Preparation chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(1-carbamyl ylmethyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.719.40C
31H
29Cl
2IN
4O
4
By chirality SFC; from racemize (2 ' R; 3R; 4 ' S)-2 '-[2-(1-carbamyl ylmethyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (0.3g) separates two enantiomorphs; chirality (2 ' R is provided; 3R; 4 ' S)-2 '-[2-(1-carbamyl ylmethyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be faint yellow solid (83mg; 28%) (RO5236850-000); and chirality (2 ' S, 3S, 4 ' R)-2 '-[2-(1-carbamyl ylmethyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone, for faint yellow solid (88mg, 29%) (RO5249057-000).
Embodiment 48a
Preparation intermediate (S)-3-methylsulfonyl oxygen base-tetramethyleneimine-1-t-butyl formate
M.W.265.33?C
10H
19NO
5S
To (S)-1-tertbutyloxycarbonyl-3-hydroxyl pyrrolidine of 0 ℃ (7.7g, 41mmol) in (Aldrich) solution in methylene dichloride (130mL), add triethylamine (10.4g, 103mmol), and methylsulfonyl chloride (8g, 70mmol, Aldrich).Reaction mixture is stirred 1h at 0 ℃, then at stirring at room 0.5h.Mixture is poured in the water, used dichloromethane extraction.Separate organic layer, water, salt water washing, MgSO
4Drying and concentrated obtains rough (S)-3-methylsulfonyl oxygen base-tetramethyleneimine-1-t-butyl formate, is yellow oil (yield 11g, 100%).
Embodiment 48b
Preparation intermediate (R/S)-3-(4-bromo-2-formyl radical-phenoxy group)-tetramethyleneimine-1-t-butyl formate
M.W.370.25?C
16H
20BrNO
4
With with in the similar mode of method described in the embodiment 4a, make the 5-bromosalicylaldehyde (3.6g, 18mmol) (Aldrich) with (S)-3-methylsulfonyl oxygen base-tetramethyleneimine-1-t-butyl formate (5.3g, 20mmol) and K
2CO
3At N, react in the dinethylformamide, obtain (R/S)-3-(4-bromo-2-formyl radical-phenoxy group)-tetramethyleneimine-1-t-butyl formate, be orange (yield 3.6g, 54%).
Embodiment 48c
Preparation intermediate (R/S)-1-[5-bromo-2-(1-tertbutyloxycarbonyl-3-pyrrolidyl oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.483.48C
2H
31BrN
2O
3Si
With with in the similar mode of method described in the embodiment 1d; with (R/S)-3-(4-bromo-2-formyl radical-phenoxy group)-tetramethyleneimine-1-t-butyl formate (2.7g; 7.4mmol) replace 4-(2-formyl radical-4-iodo-phenoxymethyl)-piperidines-1-t-butyl formate as raw material; with 1; 1,3,3; 3-hexamethyldisilazane (1.2g; 7.4mmol), just-butyllithium (2.5M, 3mL; 7.5mmol); trimethylsilyl chloride (0.8g, 7.4mmol), triethylamine (1g; 10mmol) and Acetyl Chloride 98Min. (0.79g; 10mmol) reaction obtains rough (R/S)-1-[5-bromo-2-(1-tertbutyloxycarbonyl-3-pyrrolidyl oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene; be yellow jelly, and without being used for next step with being further purified.
Embodiment 48d
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-tertbutyloxycarbonyl-3-pyrrolidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.687.42?C
33H
32BrCl
2N
3O
5
With with in the similar mode of method described in the embodiment 1e, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 5b, prepares, 3-dihydro-indoles-1-t-butyl formate (0.6g, 1.5mmol) and (R/S)-1-[5-bromo-2-(1-tertbutyloxycarbonyl-3-pyrrolidyl oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (7.4mmol) reacts 6h in 140 ℃ in toluene (30mL), obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-tertbutyloxycarbonyl-3-pyrrolidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be pale solid (yield 0.5g, 48%)
HRMS (ES
+) m/z is to C
33H
32BrCl
2N
3O
5+ H[(M+H)
+] calculated value: 700.0975.Actual measurement: 700.0973.
Embodiment 49a
Preparation intermediate (R/S)-3-(2-formyl radical-4-iodo-phenoxy group)-tetramethyleneimine-1-t-butyl formate
M.W.417.25?C
16H
20INO
4
With with in the similar mode of method described in the embodiment 4a, make 5-iodine salicylic aldehyde (5g, 20mmol) (Aldrich) and (S)-3-methylsulfonyl oxygen base-tetramethyleneimine-1-t-butyl formate of in embodiment 48a, preparing (7g, 26mmol) and K
2CO
3At N, react in the dinethylformamide, obtain (R/S)-3-(2-formyl radical-4-iodo-phenoxy group)-tetramethyleneimine-1-t-butyl formate, be white foam (yield 5g, 60%).
Embodiment 49b
Preparation intermediate (R/S)-1-[2-(1-tertbutyloxycarbonyl-3-pyrrolidyl oxygen base)-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.530.48?C
21H
31IN
2O
3Si
With with in the similar mode of method described in the embodiment 1d; with (R/S)-3-(2-formyl radical-4-iodo-phenoxy group)-tetramethyleneimine-1-t-butyl formate (4.2g; 10mmol) replace 4-(2-formyl radical-4-iodo-phenoxymethyl)-piperidines-1-t-butyl formate as raw material; with 1; 1,3,3; 3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL; 10mmol); trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.36g; 13.6mmol) and Acetyl Chloride 98Min. (1g; 13.6mmol) reaction, obtain rough (R/S)-1-[2-(1-tertbutyloxycarbonyl-3-pyrrolidyl oxygen base)-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene; be yellow jelly, and without being used for next step with being further purified.
Embodiment 49c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-tertbutyloxycarbonyl-3-pyrrolidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.748.44?C
33H
32Cl
2IN
3O
5
With with in the similar mode of method described in the embodiment 1e, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 5b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.1g, 2.8mmol) and (R/S)-1-[2-(1-tertbutyloxycarbonyl-3-pyrrolidyl oxygen base)-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (5.3g, 10mmol) in toluene (30mL), react 4h in 140 ℃, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-tertbutyloxycarbonyl-3-pyrrolidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be yellow solid (yield 0.5g, 48%)
HRMS (ES
+) m/z is to C
33H
32Cl
2IN
3O
5+ H[(M+H)
+] calculated value: 748.0837.Actual measurement: 748.0837
Embodiment 50a
Preparation intermediate 4-(4-bromo-2-formyl radical-phenoxy group)-methyl benzoate
M.W.335.16?C
15H
11BrO
4
(4.04g 20mmol) in (Alfa) solution in N,N-dimethylacetamide (30mL), adds anhydrous K to 5-bromo-2-fluorobenzaldehyde
2CO
3(2.76g, 20mmol) and the 4-methyl hydroxybenzoate (3.1g, 20mmol, Aldrich).Reaction mixture is heated 1h at 170 ℃.With the mixture cool to room temperature, with ethyl acetate dilution, water, salt water washing.Separate organic layer, use the ethyl acetate extraction water layer.Wash the organic layer of merging with water, use MgSO
4Drying concentrates.With resistates by chromatography (EtOAc: purifying hexane=1: 81: 4 then), obtain 4-(4-bromo-2-formyl radical-phenoxy group)-methyl benzoate, be white solid (yield 6.4g, 95%).
Similarly change by Marsh, G. etc. describe among the 2566-2576 at Eur.J.Org.Chem.2003.This program is slightly used with changing.
Embodiment 50b
Preparation intermediate 1-[5-bromo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.448.39 C
20H
22BrNO
4Si
With with in the similar mode of method described in the embodiment 1d; (5g is 15mmol) with 1,1 with 4-(4-bromo-2-formyl radical-phenoxy group)-methyl benzoate; 3; 3, and the 3-hexamethyldisilazane (2.4g, 15mmol); just-butyllithium (2.5M; 6mL, 15mmol), trimethylsilyl chloride (1.6g; 15mmol); triethylamine (2g, 20mmol) and Acetyl Chloride 98Min. (1.5g, 15mmol) reaction; obtain rough 1-[5-bromo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1; the 3-divinyl is yellow jelly, and without being used for next step with being further purified.
Embodiment 50c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.666.35?C
32H
23BrCl
2N
2O
5
With with in the similar mode of method described in the embodiment 32d, the E/Z-6-chloro-3-that will in embodiment 1b, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-t-butyl formate (1.1g, 2.8mmol) and 1-[5-bromo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (6.6g, 15mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is pale solid (yield 1.2g, 64%)
HRMS (ES
+) m/z is to C
32H
23BrCl
2N
2O
5+ H[(M+H)
+] calculated value: 665.0240.Actual measurement: 665.0238.
Embodiment 50d
Preparation chirality (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.666.35?C
32H
23BrCl
2N
2O
5
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (79mg) separates two enantiomorphs, and chirality (2 ' R, 3R are provided, 4 ' S)-2 '-[5-bromo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (26mg, 33%) (RO5224517-000), and chirality (2 ' S, 3S, 4 ' R)-2 '-[5-bromo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for white solid (27mg, 34%) (RO5224528-000).
Embodiment 51a
Preparation intermediate 5-bromo-2-(4-methoxyl group-phenoxy group)-phenyl aldehyde
M.W.335.16?C
15H
11BrO
3
With with in the similar mode of method described in the embodiment 50a, make 5-bromo-2-fluorobenzaldehyde (2.1g, 10mmol) (Alfa) and 4-methoxyphenol (1.24g, 10mmol) and K
2CO
3In N,N-dimethylacetamide, react, obtain 5-bromo-2-(4-methoxyl group-phenoxy group)-phenyl aldehyde, be white solid (yield 3.1g, 92%).
Embodiment 51b
Preparation intermediate 1-[5-bromo-2-(4-methoxyl group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.420.38C
19H
22BrNO
3Si
With with in the similar mode of method described in the embodiment 1d, (3.1g is 10mmol) with 1,1 to make 5-bromo-2-(4-methoxyl group-phenoxy group)-phenyl aldehyde, 3,3, and the 3-hexamethyldisilazane (1.6g, 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.36g, 13.6mmol) and Acetyl Chloride 98Min. (1.0g, 13.6mmol) reaction, obtain rough 1-[5-bromo-2-(4-methoxyl group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1, the 3-divinyl is yellow jelly, and without being used for next step with being further purified.
Embodiment 51c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-methoxyl group-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.638.34C
31H
23BrCl
2N
2O
4
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (0.6g, 1.5mmol) and 1-[5-bromo-2-(4-methoxyl group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (4.2g, 10mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-methoxyl group-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is pale solid (yield 0.61g, 64%)
HRMS (ES
+) m/z is to C
31H
23BrCl
2N
2O
4+ H[(M+H)
+] calculated value: 637.0291.Actual measurement: 637.0289.
Embodiment 52a
Preparation intermediate 5-bromo-2-(2,5-dimethyl-phenoxy group)-phenyl aldehyde
M.W.305.17C
15H
13BrO
2
With with in the similar mode of method described in the embodiment 50a, make 5-bromo-2-fluorobenzaldehyde (2.1g, 10mmol) (Alfa) and 2, the 5-xylenol (1.4g, 11mmol) and K
2CO
3In N,N-dimethylacetamide, react, obtain 5-bromo-2-(2,5-dimethyl-phenoxy group)-phenyl aldehyde, be orange (yield 3g, 98%).
Embodiment 52b
Preparation intermediate 1-[5-bromo-2-(2,5-dimethyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.418.41?C
20H
24BrNO
2Si
With with in the similar mode of method described in the embodiment 1d, make 5-bromo-2-(2,5-dimethyl-phenoxy group)-phenyl aldehyde (1.6g, 5mmol) with 1,1,3,3, the 3-hexamethyldisilazane (0.8g, 5mmol), just-butyllithium (2.5M, 2mL, 5mmol), and trimethylsilyl chloride (0.55g, 10mmol), triethylamine (0.7g, 7mmol) and Acetyl Chloride 98Min. (0.5g, 7mmol) reaction, obtain rough 1-[5-bromo-2-(2,5-dimethyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1, the 3-divinyl is yellow jelly, and without being used for next step with being further purified.
Embodiment 52c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2,5-dimethyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.636.37?C
32H
25BrCl
2N
2O
3
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (0.3g, 0.77mmol) and 1-[5-bromo-2-(2,5-dimethyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (2.2g, 5mmol) in toluene, react, react at methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2,5-dimethyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is pale solid (yield 0.38g, 78%).
HRMS (ES
+) m/z is to C
32H
25BrCl
2N
2O
3+ H[(M+H)
+] calculated value: 635.0499.Actual measurement: 635.0498.
Embodiment 53a
Preparation intermediate 4-(4-bromo-2-formyl radical-phenoxy group)-3-methoxyl group-methyl benzoate
M.W.365.18?C
16H
13BrO
5
With with in the similar mode of method described in the embodiment 50a, make 5-bromo-2-fluorobenzaldehyde (4.1g, 20mmol) (Alfa) and vanillinated methyl esters (3.64g, 20mmol) (Aldrich) and K
2CO
3In N,N-dimethylacetamide, react, obtain 4-(4-bromo-2-formyl radical-phenoxy group)-3-methoxyl group-methyl benzoate, be white solid (yield 3.1g, 92%).
Embodiment 53b
Preparation intermediate 1-[5-bromo-2-(2-methoxyl group-4-methoxycarbonyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.478.42?C
21H
24BrNO
5Si
With with in the similar mode of method described in the embodiment 1d; (3.7g is 10mmol) with 1,1 to make 4-(4-bromo-2-formyl radical-phenoxy group)-3-methoxyl group-methyl benzoate; 3; 3, and the 3-hexamethyldisilazane (1.6g, 10mmol); just-butyllithium (2.5M; 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol); triethylamine (1.36g, 13.6mmol) and Acetyl Chloride 98Min. (1.0g, 10mmol) reaction; obtain rough 1-[5-bromo-2-(2-methoxyl group-4-methoxycarbonyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1; the 3-divinyl is yellow jelly, and without being used for next step with being further purified.
Embodiment 53c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-methoxyl group-4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.696.38?C
33H
25BrCl
2N
2O
6
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.0g, 2.56mmol) and 1-[5-bromo-2-(2-methoxyl group-4-methoxycarbonyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (4.8g, 10mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-methoxyl group-4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is pale solid (yield 0.65g, 36%)
HRMS (ES
+) m/z is to C
33H
25BrCl
2N
2O
6+ H[(M+H)
+] calculated value: 695.0346.Actual measurement: 695.0346.
Embodiment 54
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-hydroxycarbonyl group-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.652.33?C
31H
21BrCl
2N
2O
5
To the racemize that in embodiment 50c, prepares (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.8g, 1.2mmol) in the solution in tetrahydrofuran (THF) (20mL), add the NaOH aqueous solution (1M) (10mL, 10mmol) and methyl alcohol (10mL).Reaction mixture at stirring at room 18h, is arrived " pH " 2 with dense HCl acidified aqueous solution then.Mixture is concentrated, between ethyl acetate and water, distribute.Separate organic layer, MgSO is used in water, salt water washing
4Drying and concentrated obtains racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-hydroxycarbonyl group-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (yield 0.6g, 74%).
HRMS (ES
+) m/z is to C
31H
21BrCl
2N
2O
5+ H[(M+H)
+] calculated value: 651.0084.Actual measurement: 651.0083.
Embodiment 55a
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-fluorine carbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.654.3?C
31H
20BrCl
2FN
2O
4
To 0 ℃ racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-hydroxycarbonyl group-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2, (0.18g 0.28mmol) in the solution in methylene dichloride (50mL), adds cyanuric fluoride (120mg to 6 ' (1H)-diketone, 0.88mmol) (Alfa) and pyridine (100mg, 1.3mmol).With mixture 0 ℃ stir 2h after, with mixture at H
2Distribute between O and the methylene dichloride.Separate organic layer and with the water layer dichloromethane extraction.Merge organic layer, use MgSO
4Dry, concentrate, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-fluorine carbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be yellow foam, and without being used for next step (yield: 0.18g, 98%) with being further purified.
Embodiment 55b
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[4-(2-hydroxyl-1,1-dimethyl-ethylamino formyl radical)-phenoxy group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.723.46?C
35H
30BrCl
2N
3O
5
To racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-fluorine carbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.18g, 0.28mmol) in the solution in tetrahydrofuran (THF) (20mL), adding 2-amino-2-methyl-third-1-alcohol (0.2g, 2.24mmol), N-methylmorpholine (0.2g, 2mmol) and 4-dimethylaminopyridine (3mg, 0.025mmol).Reaction mixture is heated 1h, cool to room temperature then in 100 ℃ under nitrogen.Mixture is diluted with ethyl acetate, with the 1N HCl aqueous solution and H
2The O washing.Separate organic layer, use Na
2SO
4Dry and concentrated.Resistates is passed through chromatography (MeOH: EtOAc=1: 19) purifying; obtain racemize (2 ' R; 3R; 4 ' S)-2 '-{ 5-bromo-2-[4-(2-hydroxyl-1; 1-dimethyl-ethylamino formyl radical)-phenoxy group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; be white solid (yield: 84mg, 42%).
HRMS (ES
+) m/z is to C
35H
30BrCl
2N
3O
5+ H[(M+H)
+] calculated value: 722.0819.Actual measurement: 722.0815.
Embodiment 56
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[4-(2-tetramethyleneimine-1-base-ethylamino formyl radical)-phenoxy group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.748.50?C
37H
33BrCl
2N
4O
4
With with in the similar mode of method described in the embodiment 55b; make racemize (2 ' R; 3R; 4 ' S)-2 '-[5-bromo-2-(4-fluorine carbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (0.18g; 0.28mmol) and N-(2-amino-ethyl) tetramethyleneimine (0.4g; 3.5mmol); N-methylmorpholine and 4-dimethylaminopyridine react in tetrahydrofuran (THF); obtain racemize (2 ' R, 3R, 4 ' S)-2 '-{ 5-bromo-2-[4-(2-tetramethyleneimine-1-base-ethylamino formyl radical)-phenoxy group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.17g, 83%).
HRMS (ES
+) m/z is to C
37H
33BrCl
2N
4O
4+ H[(M+H)
+] calculated value: 747.1135.Actual measurement: 747.1133.
Embodiment 57
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-formamyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.651.34?C
31H
22BrCl
2N
3O
4
Racemize (2 ' the R that will in embodiment 55a, prepare, 3R, 4 ' S)-2 '-[5-bromo-2-(4-fluorine carbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.14g, 0.21mmol) the methanol solution of ammonia (7N, 10mL) in stirring at room 18h.Reaction mixture is concentrated; and resistates is passed through chromatography purification (EtOAc: MeOH=19: 1); obtain racemize (2 ' R; 3R; 4 ' S)-2 '-[5-bromo-2-(4-formamyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; be yellow solid (yield 0.11g, 80%).
HRMS (ES
+) m/z is to C
31H
22BrCl
2N
3O
4+ H[(M+H)
+] calculated value: 650.0244, the actual measurement: 650.0246.
Embodiment 58a
Preparation intermediate 4-(4-bromo-2-formyl radical-phenoxy group)-3-chloro-methyl benzoate
M.W.369.60?C
15H
10BrClO
4
With with in the similar mode of method described in the embodiment 50a, make 5-bromo-2-fluorobenzaldehyde (4.1g, 20mmol) (Alfa) and 3-chloro-4-methyl hydroxybenzoate (4g, 21mmol) (Lancaster) and K
2CO
3In N,N-dimethylacetamide, react, obtain 4-(4-bromo-2-formyl radical-phenoxy group)-3-chloro-methyl benzoate, be pale solid (yield 3.7g, 50%).
Embodiment 58b
Preparation intermediate 1-[5-bromo-2-(2-chloro-4-methoxycarbonyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.482.84?C
20H
21BrClNO
4Si
With with in the similar mode of method described in the embodiment 1d, (3.7g is 10mmol) with 1 to make 4-(4-bromo-2-formyl radical-phenoxy group)-3-chloro-methyl benzoate; 1; 1,3,3; 3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL; 10mmol); trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.36g; 13.6mmol) and Acetyl Chloride 98Min. (1.0g; 13.6mmol) reaction, obtain rough 1-[5-bromo-2-(2-chloro-4-methoxycarbonyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene; be yellow jelly, and without being used for next step with being further purified.
Embodiment 58c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-chloro-4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.700.80?C
32H
22BrCl
3N
2O
5
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (0.6g, 1.53mmol) and 1-[5-bromo-2-(2-methoxyl group-4-methoxycarbonyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (4.6g, 9.5mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-chloro-4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is yellow solid (yield 0.6g, 56%)
HRMS (ES
+) m/z is to C
32H
22BrCl
3N
2O
5+ H[(M+H)
+] calculated value: 698.9851.Actual measurement: 698.9845.
Embodiment 59a
Preparation intermediate 4-(4-chloro-2-formyl radical-phenoxy group)-methyl benzoate
M.W.290.71?C
15H
11ClO
4
With with in the similar mode of method described in the embodiment 50a, make 5-chloro-2-fluorobenzaldehyde (4.2g, 26mmol) (Alfa) and 4-methyl hydroxybenzoate (4g, 28mmol) (Aldrich) and K
2CO
3In N,N-dimethylacetamide, react, obtain 4-(4-chloro-2-formyl radical-phenoxy group)-methyl benzoate, be white solid (yield 6.1g, 80%).
Embodiment 59b
Preparation intermediate 1-[5-chloro-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.403.94?C
20H
22ClNO
4Si
With with in the similar mode of method described in the embodiment 1d; (2.9g is 10mmol) with 1,1 to make 4-(4-chloro-2-formyl radical-phenoxy group)-methyl benzoate; 3; 3, and the 3-hexamethyldisilazane (1.6g, 10mmol); just-butyllithium (2.5M; 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol); triethylamine (1.36g, 13.6mmol) and Acetyl Chloride 98Min. (1.0g, 10mmol) reaction; obtain rough 1-[5-chloro-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1; the 3-divinyl is yellow jelly, and without being used for next step with being further purified.
Embodiment 59c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.621.90?C
32H
23Cl
3N
2O
5
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.0g, 2.56mmol) and 1-[5-chloro-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (4g, 9.9mmol) in toluene, react, react then with in the trifluoroacetic acid methylene dichloride, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is pale solid (yield 1.2g, 75%)
HRMS (ES
+) m/z is to C
32H
23Cl
3N
2O
5+ H[(M+H)
+] calculated value: 621.0746.Actual measurement: 621.0744.
Embodiment 60a
Preparation intermediate 4-(2-hydroxyl-oxyethyl group)-phenol
M.W.154.17?C
8H
10O
3
To 0 ℃ 4-hydroxyphenoxy acetate (4.9g, 29mmol) in (Aldrich) solution in anhydrous tetrahydro furan (30mL), drip the borine tetrahydrofuran (THF) (1M, 90mL, 90mmol).Then with reaction mixture at stirring at room 2h.Mixture is concentrated and resistates is distributed between ethyl acetate and water.Separate organic layer, use the salt water washing, use MgSO
4Drying and concentrated obtains title compound, is yellow oil (4.2g, 94%)
Embodiment 60b
Preparation intermediate 4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenol
M.W.268.43?C
14H
24O
3Si
To 0 ℃ 4-(2-hydroxyl-oxyethyl group)-phenol (4.2g, 27mmol) at anhydrous N, in the solution in the dinethylformamide (30mL), add imidazoles (2.1g, 31mmol) and TERT-BUTYL DIMETHYL CHLORO SILANE (4g, 27mmol).Then reaction mixture is stirred 1h at 0 ℃.Mixture is distributed between ethyl acetate and water.Separate organic layer, with the water layer ethyl acetate extraction.MgSO is used in the organic layer water and the salt water washing that merge
4Drying and concentrated.Resistates is passed through chromatography (EtOAc: hexane=1; 4) purifying obtains 4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenol, be colorless oil (5.1g, 70%)
Embodiment 60c
Preparation intermediate 2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-5-iodo-phenyl aldehyde
M.W.384.17?C
15H
13IO
4
With with in the similar mode of method described in the embodiment 50a, make 2-fluoro-5-benzaldehyde iodine (2.5g, 10mmol) (Aldrich) and 4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenol (2.7g, 10mmol) and K
2CO
3In N,N-dimethylacetamide,, obtain 2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group in 170 ℃ of reaction 0.5h]-5-iodo-phenyl aldehyde, be yellow solid (yield 3.8g, 98%).
Embodiment 60d
Preparation intermediate 2-{4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenoxy group }-5-iodo-phenyl aldehyde
M.W.498.44?C
21H
27IO
4Si
With with in the similar mode of method described in the embodiment 60b, make 2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-5-iodo-phenyl aldehyde (3.8g, 9.8mmol) and TERT-BUTYL DIMETHYL CHLORO SILANE (1.8g, 12mmol) and imidazoles at N, react in the dinethylformamide, obtain 2-{4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenoxy group }-5-iodo-phenyl aldehyde, be white solid (yield 4.7g, 95%).
Embodiment 60e
Preparation intermediate 1-{2-{4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenoxy group }-5-iodo-phenyl }-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.611.67?C
26H
38INO
4Si
2
With with in the similar mode of method described in the embodiment 1d, make 2-{4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenoxy group }-5-iodo-phenyl aldehyde (4.7g, 9.4mmol) with 1,1,3,3, and the 3-hexamethyldisilazane (1.6g, 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.36g, 13.6mmol) and Acetyl Chloride 98Min. (1.0g, 10mmol) reaction, obtain rough 1-{2-{4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenoxy group }-5-iodo-phenyl }-3-trimethylsiloxy-2-azepine-1, the 3-divinyl is yellow jelly, and without being used for next step with being further purified.
Embodiment 60f
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-5-iodo-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.715.37?C
32H
25Cl
2IN
2O
5
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.0g, 2.56mmol) and 1-{2-{4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenoxy group }-5-iodo-phenyl }-3-trimethylsiloxy-2-azepine-1,3-divinyl (5g, 8.2mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-5-iodo-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is faint yellow solid (yield 0.9g, 49%)
HRMS (ES
+) m/z is to C
32H
25Cl
2IN
2O
5+ H[(M+H)
+] calculated value: 715.0258.Actual measurement: 715.0258.
Embodiment 60g
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-5-iodo-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.715.37?C
32H
25Cl
2IN
2O
5
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-5-iodo-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (220mg) separates two enantiomorphs, and chirality (2 ' R, 3R are provided, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-5-iodo-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be yellow solid (93mg, 42%) (RO5250875-000), and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-5-iodo-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for yellow solid (87mg, 40%) (RO5250874-000).
Embodiment 61a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.613.49?C
34H
26Cl
2N
2O
5
With with in the similar mode of method described in the embodiment 2, make racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-5-iodo-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.9g, 1.26mmol) and trimethyl silyl acetylene (0.25g, 2.5mmol), CuI (0.48g, 2.5mmol), triethylamine (0.25g, 2.5mmol) and dichloro two (triphenylphosphine) palladium (0) (0.18g, 0.025mmol) in tetrahydrofuran (THF), react, in methyl alcohol, handle then with the NaOH aqueous solution, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be pale solid (yield 0.58g, 75%).
HRMS (ES
+) m/z is to C
34H
26Cl
2N
2O
5+ H[(M+H)
+] calculated value: 613.1292.Actual measurement: 613.1289.
Embodiment 61b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.613.49?C
34H
26Cl
2N
2O
5
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (550mg) separates two enantiomorphs, chirality (2 ' R is provided, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be pale solid (195mg, 36%) (RO5246718-000), and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for pale solid (183mg, 30%) (RO5246719-000).
Embodiment 62a
Preparation intermediate 5-chloro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl aldehyde
M.W.292.72?C
15H
13ClO
4
With with in the similar mode of method described in the embodiment 50a, make 5-chloro-2-fluorobenzaldehyde (1.2g, 7.6mmol) (Aldrich) with 4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group of in embodiment 60b, preparing]-phenol (2.1g, 7.8mmol) and K
2CO
3In N,N-dimethylacetamide,, obtain 5-chloro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group in 170 ℃ of reaction 0.5h]-phenyl aldehyde, be colorless oil (yield 1.68g, 75%).
Embodiment 62b
Preparation intermediate 2-{4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenoxy group }-5-chloro-phenyl aldehyde
M.W.406.99?C
21H
27ClO
4Si
With with in the similar mode of method described in the embodiment 60b, make 5-chloro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl aldehyde (1.68g, 5.7mmol) and TERT-BUTYL DIMETHYL CHLORO SILANE (1.3g, 8.6mmol) and imidazoles at N, react in the dinethylformamide, obtain 2-{4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenoxy group }-5-chloro-phenyl aldehyde, be white solid (yield 2.1g, 90%).
Embodiment 62c
Preparation intermediate 1-{2-{4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenoxy group }-5-chloro-phenyl }-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.520.22?C
26H
38ClNO
4Si
2
With with in the similar mode of method described in the embodiment 1d, make 2-{4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenoxy group }-5-chloro-phenyl aldehyde (2.1g, 5.1mmol) with 1,1,3,3, and the 3-hexamethyldisilazane (0.8g, 5mmol), just-butyllithium (2.5M, 2mL, 5mmol), trimethylsilyl chloride (0.55g, 5mmol), triethylamine (0.68g, 6.8mmol) and Acetyl Chloride 98Min. (0.5g, 6.8mmol) reaction, obtain rough 1-{2-{4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenoxy group }-5-chloro-phenyl }-3-trimethylsiloxy-2-azepine-1, the 3-divinyl is yellow jelly, and without being used for next step with being further purified.
Embodiment 62d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-5-chloro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl }-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.623.92?C
32H
25Cl
3N
2O
5
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (0.4g, 1.03mmol) and 1-{2-{4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenoxy group }-5-chloro-phenyl }-3-trimethylsiloxy-2-azepine-1,3-divinyl (2.5g, 4.8mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-5-chloro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl }-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is faint yellow solid (yield 0.36g, 57%)
HRMS (ES
+) m/z is to C
32H
25Cl
3N
2O
5+ H[(M+H)
+] calculated value: 623.0902.Actual measurement: 623.0900.
Embodiment 62e
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-5-chloro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl }-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.623.92?C
32H
25Cl
3N
2O
5
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-5-chloro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl }-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (200mg) separates two enantiomorphs, and chirality (2 ' R, 3R are provided, 4 ' S)-6-chloro-2 '-5-chloro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl }-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be yellow solid (84mg, 42%) (RO5249565-000), and chirality (2 ' S, 3S, 4 ' R)-6-chloro-2 '-5-chloro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl }-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for yellow solid (77mg, 39%) (RO5249599-000).
Embodiment 63a
Preparation intermediate 5-bromo-2-(2,6-dimethyl-pyridin-4-yl oxygen base)-phenyl aldehyde
M.W.306.16?C
14H
12BrNO
2
With with in the similar mode of method described in the embodiment 50a, make 5-bromo-2-fluorobenzaldehyde (4.1g, 20mmol) (Alfa) and 2,6-dimethyl-4-pyridone (2.5g, 20mmol) and K
2CO
3In N,N-dimethylacetamide, react, obtain 5-bromo-2-(2,6-dimethyl-pyridin-4-yl oxygen base)-phenyl aldehyde, be pale solid (yield 6g, 98%).
Embodiment 63b
Preparation intermediate 1-[5-bromo-2-(2,6-dimethyl-pyridin-4-yl oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.419.40?C
19H
23BrN
2O
2Si
With with in the similar mode of method described in the embodiment 1d, make 5-bromo-2-(2,6-dimethyl-pyridin-4-yl oxygen base)-phenyl aldehyde (3.1g, 10mmol) with 1,1,1,3,3,3-hexamethyldisilazane (1.6g, 10mmol), just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol), and triethylamine (1.36g, 13.6mmol) and Acetyl Chloride 98Min. (1.0g, 13.6mmol) reaction, obtain rough 1-[5-bromo-2-(2,6-dimethyl-pyridin-4-yl oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 63c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2,6-dimethyl-4-pyridyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.637.36?C
31H
24BrCl
2N
3O
3
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.0g, 2.56mmol) and 1-[5-bromo-2-(2,6-dimethyl-pyridin-4-yl oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (4.2g, 10mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2,6-dimethyl-4-pyridyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (yield 0.99g, 61%)
HRMS (ES
+) m/z is to C
31H
24BrCl
2N
3O
3+ H[(M+H)
+] calculated value: 636.0451.Actual measurement: 636.0454.
Embodiment 64a
Preparation intermediate 5-chloro-2-iodo-phenyl aldehyde
M.W.266.47?C
7H
4ClIO
To 0 ℃ 5-chloro-2-iodo-benzoic acid (4.92g, 17mmol) in (TRANS) solution in anhydrous tetrahydro furan (100mL), drip the borine tetrahydrofuran (THF) (1M, 34mL, 34mmol).Then with reaction mixture at stirring at room 18h.Mixture is concentrated and resistates is distributed between ethyl acetate and water.Separate organic layer, use the salt water washing, MgSO
4Drying and concentrated obtains colorless oil.This oily matter is dissolved in 1,2-ethylene dichloride (50mL), and add activatory MnO
2(15g).Then mixture is heated 2h under refluxing, cool to room temperature, and by the short pad filtration of diatomite.Filtrate concentrated and by chromatography (EtOAc: hexane=1; 8) purifying obtains 5-chloro-2-iodo-phenyl aldehyde, is white solid (yield 5.5g, 25%).
Embodiment 64b
Preparation intermediate 1-(5-chloro-2-iodophenyl)-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.379.70?C
12H
15ClINOSi
With with in the similar mode of method described in the embodiment 5d, the 5-chloro-2-benzaldehyde iodine (3.97g that will in embodiment 23a, prepare, 15mmol) replace 2-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-5-iodo-phenyl aldehyde is as raw material, with 1,1,3,3,3-hexamethyldisilazane (2.4g, 15mmol), just-butyllithium (2.5M, 6mL, 15mmol), trimethylsilyl chloride (1.6g, 15mmol), triethylamine (2g, 20mmol) and Acetyl Chloride 98Min. (1.5g, 20mmol) reaction obtains rough 1-(5-chloro-2-iodophenyl)-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 64c
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-chloro-2-iodophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.597.67?C
24H
16Cl
3IN
2O
2
With with in the similar mode of method described in the embodiment 7b, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (2g, 5.6mmol) with embodiment 23b in rough 1-(5-chloro-2-iodophenyl)-3-trimethylsiloxy-2-azepine-1 of preparing, 3-divinyl (5.6g, 15mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-chloro-2-iodophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is yellow solid (yield 2.1g, 63%)
HRMS (ES
+) m/z is to C
24H
16Cl
3IN
2O
2+ H[(M+H)
+] calculated value: 596.9395.Actual measurement: 596.9393.
Embodiment 64d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(5-chloro-2-imidazoles-1-base-phenyl)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.537.83?C
27H
19Cl
3N
4O
2
To racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-chloro-2-iodophenyl) spiral shell [3H-indoles-3,3 '-piperidines] (0.3g is 0.5mmol) at anhydrous N for-2,6 ' (1H)-diketone, in the solution in the dinethylformamide (10mL), add Cs
2CO
3(1.2g, 4mmol) (Aldrich), CuI (95mg, 0.5mmol) (Aldrich), N, N, N ', N '-Tetramethyl Ethylene Diamine (0.2mL, 2mmol), and imidazoles (80mg, 1mmol).Mixture is heated 0.5h in 170 ℃ under nitrogen.With the mixture cool to room temperature, between ethyl acetate and water, distribute.Separate organic layer, and with the water layer ethyl acetate extraction.Merge organic layer, use the salt water washing, use MgSO
4Drying and concentrated.Resistates is passed through chromatography (EtOAc: MeOH=9: 1) purifying, obtain raw product 997mg), it is further purified with RP-HPLC, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(5-chloro-2-imidazoles-1-base-phenyl)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (yield 16mg).
HRMS (ES
+) m/z is to C
27H
19Cl
3N
4O
2+ H[(M+H)
+] calculated value: 537.0647.Actual measurement: 537.0646.
Embodiment 65a
Preparation intermediate 4-(2-formyl radical-4-iodo-phenoxy group)-benzonitrile
M.W.349.13?C
14H
8INO
2
With with in the similar mode of method described in the embodiment 50a, with 2-fluoro-5-benzaldehyde iodine (2g, 8mmol) (Aldrich) and 4-cyanophenol (1.43g, 12mmol) and K
2CO
3In N,N-dimethylacetamide, react, obtain 4-(2-formyl radical-4-iodo-phenoxy group)-benzonitrile, be faint yellow solid (yield 1.9g, 70.4%).
Embodiment 65b
Preparation intermediate 1-[2-(4-cyano group-phenoxy group)-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.462.37?C
19H
19IN
2O
2Si
With with in the similar mode of method described in the embodiment 1d, (1.9g is 5.44mmol) with 1 with 4-(2-formyl radical-4-iodo-phenoxy group)-benzonitrile; 1; 1,3,3; 3-hexamethyldisilazane (1.13mL; 5.44mmol), just-butyllithium (2.5M, 2.18mL; 5.45mmol); trimethylsilyl chloride (0.69mL, 5.44mmol), triethylamine (0.98mL; 7.07mmol) and Acetyl Chloride 98Min. (0.66mL; 7.07mmol) reaction, obtain rough 1-[2-(4-cyano group-phenoxy group)-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene; be yellow jelly, and without being used for next step with being further purified.
Embodiment 65c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 ' (3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.680.32?C
31H
20Cl
2IN
3O
3
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (0.85g, 2.18mmol) and 1-[2-(4-cyano group-phenoxy group)-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (5.44mmol) reacts in toluene, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.8g, 54%)
HRMS (ES
+) m/z is to C
31H
20Cl
2IN
3O
3+ H[(M+H)
+] calculated value: 679.9999.Actual measurement: 679.9999.
Embodiment 65d
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.680.32?C
31H
20Cl
2IN
3O
3
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (500mg) separates two enantiomorphs, and chirality (2 ' R, 3R are provided, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (0.23g, 46%) (RO5249341-000), and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for white solid (0.21g, 42%) (RO5249340-000).
Embodiment 66a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.578.45?C
33H
21Cl
2N
3O
3
With with in the similar mode of method described in the embodiment 6a, make racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.65g, 0.96mmol) and trimethyl silyl acetylene (0.94g, 9.6mmol), CuI (10mg), triethylamine (2.89g, 28.7mmol), (53.6mg 0.077mmol) at anhydrous N, reacts in the dinethylformamide with dichloro two (triphenylphosphine) palladium (0), in methyl alcohol, handle then with the NaOH aqueous solution, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is pale solid (yield 0.285g, 51%)
HRMS (ES
+) m/z is to C
33H
21Cl
2N
3O
3+ H[(M+H)
+] calculated value: 578.1033.Actual measurement: 578.1030.
Embodiment 66b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.578.45?C
33H
21Cl
2N
3O
3
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (260mg) separates two enantiomorphs, and chirality (2 ' R, 3R are provided, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (98mg, 38%) (RO5249051-000), and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for white solid (102mg, 39%) (RO5249050-000).
Embodiment 67a
Preparation intermediate 5-iodo-2-(4-methoxyl group-phenoxy group)-phenyl aldehyde
M.W.354.15?C
14H
10IO
3
With with in the similar mode of method described in the embodiment 50a, make 2-fluoro-5-benzaldehyde iodine (1.2g, 4.8mmol) (Aldrich) and 4-methoxyphenol (0.71g, 5.76mmol) and K
2CO
3In N,N-dimethylacetamide, react, obtain 5-iodo-2-(4-methoxyl group-phenoxy group)-phenyl aldehyde, be yellow oil (yield 1.12g, 66%).
Embodiment 67b
Preparation intermediate 1-[5-iodo-2-(4-methoxyl group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.467.38?C
19H
22INO
3Si
With with in the similar mode of method described in the embodiment 1d, (1.12g is 3.16mmol) with 1 to make 5-iodo-2-(4-methoxyl group-phenoxy group)-phenyl aldehyde, 1,1,3,3,3-hexamethyldisilazane (0.66mL, 3.16mmol), just-butyllithium (2.5M, 1.26mL, 3.16mmol), trimethylsilyl chloride (0.4mL, 3.16mmol), triethylamine (0.57mL, 4.1mmol) and Acetyl Chloride 98Min. (0.39mL, 4.1mmol) reaction, obtain rough 1-[5-iodo-2-(4-methoxyl group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 67c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-methoxyl group-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.685.34?C
31H
23Cl
2IN
2O
4
With with in the similar mode of method described in the embodiment 32d, the E/Z-6-chloro-3-that will in embodiment 1b, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-t-butyl formate (0.49g, 1.26mmol) and 1-[5-iodo-2-(4-methoxyl group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (3.16mmol) reacts in toluene, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-methoxyl group-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.35g, 41%)
HRMS (ES
+) m/z is to C
31H
23Cl
2IN
2O
4+ H[(M+H)
+] calculated value: 685.0153.Actual measurement: 685.0155.
Embodiment 68a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-methoxyl group-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.?583.47?C
33H
24Cl
2N
2O
4
With with in the similar mode of method described in the embodiment 6a, with racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-methoxyl group-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.29g, 0.42mmol) and trimethyl silyl acetylene (0.41g, 4.2mmol), CuI (5mg), triethylamine (1.76mL, 12.7mmol), (23.4mg 0.034mmol) at anhydrous N, reacts in the dinethylformamide with dichloro two (triphenylphosphine) palladium (0), in methyl alcohol, handle then with the NaOH aqueous solution, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-methoxyl group-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (yield 0.15g, 61%)
HRMS (ES
+) m/z is to C
33H
24Cl
2N
2O
4+ H[(M+H)
+] calculated value: 583.1186.Actual measurement: 583.1187.
Embodiment 68b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-methoxyl group-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.583.47?C
33H
24Cl
2N
2O
4
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-methoxyl group-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (500mg) separates two enantiomorphs, and chirality (2 ' R, 3R are provided, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-methoxyl group-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be faint yellow solid (0.24g, 48%) (RO5249052-000), and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-methoxyl group-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for faint yellow solid (0.24g, 48%) (RO5249053-000).
Embodiment 69a
Preparation intermediate 4-(2-formyl radical-4-iodo-phenoxy group)-methyl benzoate
M.W.382.16?C
15H
11IO
4
With with in the similar mode of method described in the embodiment 50a, with 2-fluoro-5-benzaldehyde iodine (3.6g, 14.4mmol) (Aldrich) and 4-methyl hydroxybenzoate (2.62g, 17.3mmol) and K
2CO
3In N,N-dimethylacetamide, react, obtain 4-(2-formyl radical-4-iodo-phenoxy group)-methyl benzoate, be yellow oil (yield 3.8g, 69%).
Embodiment 69b
Preparation intermediate 1-[5-iodo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.495.39?C
20H
22INO
4Si
With with in the similar mode of method described in the embodiment 1d, (3.8g is 9.94mmol) with 1 to make 4-(2-formyl radical-4-iodo-phenoxy group)-methyl benzoate; 1; 1,3,3; 3-hexamethyldisilazane (2.06mL; 9.94mmol), just-butyllithium (2.5M, 3.97mL; 9.94mmol); trimethylsilyl chloride (1.26mL, 9.94mmol), triethylamine (1.79mL; 12.9mmol) and Acetyl Chloride 98Min. (1.22mL; 12.9mmol) reaction, obtain rough 1-[5-iodo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene; be yellow jelly, and without being used for next step with being further purified.
Embodiment 69c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-methoxycarbonyl-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.713.35?C
32H
23Cl
2IN
2O
5
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.55g, 3.98mmol) and 1-[5-iodo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (9.94mmol) reacts in toluene, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-methoxycarbonyl-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 1.5g, 53%)
HRMS (ES
+) m/z is to C
32H
23Cl
2IN
2O
5+ H[(M+H)
+] calculated value: 713.0102.Actual measurement: 713.0102.
Embodiment 70
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-methoxycarbonyl-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.611.48?C
34H
24Cl
2N
2O
5
With with in the similar mode of method described in the embodiment 6a, make racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-methoxycarbonyl-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.45g, 0.63mmol) and trimethyl silyl acetylene (0.45g, 6.3mmol), CuI (3mg), triethylamine (2.63mL, 18.9mmol), (35.3mg 0.05mmol) at anhydrous N, reacts in the dinethylformamide with dichloro two (triphenylphosphine) palladium (0), in methyl alcohol, handle then with the NaOH aqueous solution, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-methoxycarbonyl-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (yield 0.28g, 73%)
HRMS (ES
+) m/z is to C
34H
24Cl
2N
2O
5+ H[(M+H)
+] calculated value: 611.1135.Actual measurement: 611.1134.
Embodiment 71
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-hydroxycarbonyl group-phenoxy group)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.699.32?C
31H
21Cl
2IN
2O
5
With with in the similar mode of method described in the embodiment 54, make racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-methoxycarbonyl-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.68g, 0.95mmol) and LiOH (0.41g, aqueous solution 9.5mmol) reacts in tetrahydrofuran (THF) and methyl alcohol, obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-hydroxycarbonyl group-phenoxy group)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.5g, 75%).
HRMS (ES
+) m/z is to C
31H
21Cl
2IN
2O
5+ H[(M+H)
+] calculated value: 698.9945.Actual measurement: 698.9941.
Embodiment 72a
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(4-formamyl-phenoxy group)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.698.35?C
31H
22Cl
2IN
3O
4
With with in the similar mode of method described in the embodiment 47a, make racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-hydroxycarbonyl group-phenoxy group)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines] (0.4g is 0.57mmol) with EDCI (0.22g for-2,6 ' (1H)-diketone, 1.14mmol), HOBT (0.154g, 1.14mmol), diisopropyl ethyl amine (0.29g, 2.28mmol), NH
4Cl (60mg; 1.14mmol) at N; react in the dinethylformamide; obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(4-formamyl-phenoxy group)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.35g, 88%)
Embodiment 72b
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(4-formamyl-phenoxy group)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.596.47?C
33H
23Cl
2N
3O
4
With with in the similar mode of method described in the embodiment 6a; make racemize (2 ' R; 3R; 4 ' S)-2 '-[2-(4-formamyl-phenoxy group)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (0.35g; 0.5mmol) and trimethyl silyl acetylene (0.49g; 5mmol), CuI (3mg), triethylamine (1.52mL; 15mmol); (28mg 0.04mmol) at anhydrous N, reacts in the dinethylformamide with dichloro two (triphenylphosphine) palladium (0); in methyl alcohol, handle then with the NaOH aqueous solution; obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(4-formamyl-phenoxy group)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (yield 0.25g, 84%)
HRMS (ES
+) m/z is to C
33H
23Cl
2N
3O
4+ H[(M+H)
+] calculated value: 596.1139.Actual measurement: 596.1135.
Embodiment 72c
Preparation chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(4-formamyl-phenoxy group)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.596.47?C
33H
23Cl
2N
3O
4
By chirality SFC; from racemize (2 ' R; 3R; 4 ' S)-2 '-[2-(4-formamyl-phenoxy group)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (300mg) separates two enantiomorphs; chirality (2 ' R is provided; 3R; 4 ' S)-2 '-[2-(4-formamyl-phenoxy group)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be pale solid (111mg; 37%) (RO5247924-000); and chirality (2 ' S, 3S, 4 ' R)-2 '-[2-(4-formamyl-phenoxy group)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone, for pale solid (112mg, 37%) (RO5247926-000).
Embodiment 73a
Preparation intermediate 2-(2,6-dimethyl-pyridin-4-yl oxygen base)-5-iodo-phenyl aldehyde
M.W.353.16?C
14H
12INO
2
With with in the similar mode of method described in the embodiment 50a, make 2-fluoro-5-benzaldehyde iodine (2g, 8mmol) (Aldrich) and 2,6-dimethyl-4-pyridone (1.08g, 8.8mmol) and K
2CO
3In N,N-dimethylacetamide, react, obtain 2-(2,6-dimethyl-pyridin-4-yl oxygen base)-5-iodo-phenyl aldehyde, be yellow solid (yield 2.63g, 92%).
Embodiment 73b
Preparation intermediate 1-[2-(2,6-dimethyl-pyridin-4-yl oxygen base)-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.466.40?C
19H
23IN
2O
2Si
With with in the similar mode of method described in the embodiment 1d, make 2-(2,6-dimethyl-pyridin-4-yl oxygen base)-5-iodo-phenyl aldehyde (2.63g, 7.4mmol) with 1,1,1,3,3,3-hexamethyldisilazane (1.55mL, 7.4mmol), just-and butyllithium (2.5M, 2.98mL, 7.4mmol), trimethylsilyl chloride (0.945mL, 7.4mmol), triethylamine (1.34mL, 9.7mmol) and Acetyl Chloride 98Min. (0.68mL, 9.7mmol) reaction, obtain rough 1-[2-(2,6-dimethyl-pyridin-4-yl oxygen base)-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 73c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2,6-dimethyl-4-pyridyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.684.49?C
31H
24Cl
2IN
3O
3
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.15g, 2.96mmol) and 1-[2-(2,6-dimethyl-pyridin-4-yl oxygen base)-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (7.4mmol) reacts in toluene, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2,6-dimethyl-4-pyridyl oxygen base)-and 5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.8g, 39%)
HRMS (ES
+) m/z is to C
31H
24Cl
2IN
3O
3+ H[(M+H)
+] calculated value: 684.0312.Actual measurement: 684.0315.
Embodiment 74
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2,6-dimethyl-4-pyridyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.582.49?C
33H
25Cl
2N
3O
3
With with in the similar mode of method described in the embodiment 6a, make racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2,6-dimethyl-4-pyridyl oxygen base)-and 5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines] (0.62g is 0.9mmol) with trimethyl silyl acetylene (0.89g for-2,6 ' (1H)-diketone, 9mmol), CuI (5mg), and triethylamine (2.74g, 27mmol), with dichloro two (triphenylphosphine) palladium (0) (50.7mg, 0.07mmol) at anhydrous N, react in the dinethylformamide, in methyl alcohol, handle then with the NaOH aqueous solution, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2,6-dimethyl-4-pyridyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is light yellow solid (yield 0.28g, 53%)
HRMS (ES
+) m/z is to C
33H
25Cl
2N
3O
3+ H[(M+H)
+] calculated value: 582.1346.Actual measurement: 582.1346.
Embodiment 75a
Preparation intermediate 5-bromo-2-(4-fluoro-phenoxy group)-phenyl aldehyde
M.W.295.11?C
13H
8BrFO
2
With with in the similar mode of method described in the embodiment 50a, make 5-bromo-2-fluorobenzaldehyde (4.1g, 20mmol) (Alfa) and 4-fluorophenol (2.5g, 22mmol) (Aldrich) and K
2CO
3In N,N-dimethylacetamide, react, obtain 5-bromo-2-(4-fluoro-phenoxy group)-phenyl aldehyde, be yellow solid (yield 5.8g, 97%).
Embodiment 75b
Preparation intermediate 1-[5-bromo-2-(4-fluoro-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.408.35?C
18H
19BrFNO
2Si
With with in the similar mode of method described in the embodiment 1d, (5.8g is 20mmol) with 1 to make 5-bromo-2-(4-fluoro-phenoxy group)-phenyl aldehyde, 1,1,3,3,3-hexamethyldisilazane (4.1mL, 20mmol), just-butyllithium (2.5M, 8mL, 20mmol), trimethylsilyl chloride (2.5mL, 20mmol), triethylamine (3.55mL, 25mmol) and Acetyl Chloride 98Min. (1.8mL, 25.5mmol) reaction, obtain rough 1-[5-bromo-2-(4-fluoro-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 75c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-fluoro-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.626.31?C
30H
20BrCl
2FN
2O
3
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (3.1g, 7.8mmol) and 1-[5-bromo-2-(4-fluoro-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (20mmol) reacts in toluene, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-fluoro-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.67g, 14%)
HRMS (ES
+) m/z is to C
30H
20BrCl
2FN
2O
3+ H[(M+H)
+] calculated value: 625.0091.Actual measurement: 625.0094.
Embodiment 76a
Preparation intermediate 5-bromo-2-(4-trifluoromethyl-phenoxy group)-phenyl aldehyde
M.W.345.12?C
14H
8BrF
3O
2
With with in the similar mode of method described in the embodiment 50a, make 5-bromo-2-fluorobenzaldehyde (2.1g, 11mmol) (Alfa) and 4-trifloro methyl phenol (1.9g, 12mmol) (Aldrich) and K
2CO
3In N,N-dimethylacetamide, react, obtain 5-bromo-2-(4-trifluoromethyl-phenoxy group)-phenyl aldehyde, be yellow solid (yield 2.47g, 68%).
Embodiment 76b
Preparation intermediate 1-[5-bromo-2-(4-trifluoromethyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.458.35?C
19H
19BrF
3NO
2Si
With with in the similar mode of method described in the embodiment 1d, (2.47g is 7mmol) with 1 to make 5-bromo-2-(4-trifluoromethyl-phenoxy group)-phenyl aldehyde, 1,1,3,3,3-hexamethyldisilazane (1.5mL, 7mmol), just-butyllithium (2.5M, 2.9mL, 7mmol), trimethylsilyl chloride (0.9mL, 7mmol), triethylamine (1.3mL, 9mmol) and Acetyl Chloride 98Min. (0.5mL, 9mmol) reaction obtains rough 1-[5-bromo-2-(4-trifluoromethyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 76c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-trifluoromethyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.676.31?C
31H
20BrCl
2F
3N
2O
3
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.1g, 2.8mmol) and 1-[5-bromo-2-(4-trifluoromethyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (7mmol) reacts in toluene, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-trifluoromethyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.3g, 16%)
HRMS (ES
+) m/z is to C
31H
20BrCl
2F
3N
2O
3+ H[(M+H)
+] calculated value: 675.0059.Actual measurement: 675.0060.
Embodiment 77a
Preparation intermediate 5-chloro-2-(4-trifluoromethyl-phenoxy group)-phenyl aldehyde
M.W.300.67?C
14H
8ClF
3O
2
With with in the similar mode of method described in the embodiment 50a, make 5-chloro-2-fluorobenzaldehyde (0.88g, 5.6mmol) (Beta Pharma) and 4-trifloro methyl phenol (1g, 6.6mmol) (Aldrich) and K
2CO
3In N,N-dimethylacetamide, react, obtain 5-chloro-2-(4-trifluoromethyl-phenoxy group)-phenyl aldehyde, be yellow solid (yield 0.98g, 58%).
Embodiment 77b
Preparation intermediate 1-[5-chloro-2-(4-trifluoromethyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.413.90?C
19H
19ClF
3NO
2Si
With with in the similar mode of method described in the embodiment 1d, (0.98g is 3.3mmol) with 1 to make 5-chloro-2-(4-trifluoromethyl-phenoxy group)-phenyl aldehyde, 1,1,3,3,3-hexamethyldisilazane (0.67mL, 3.3mmol), just-butyllithium (2.5M, 1.3mL, 3.3mmol), trimethylsilyl chloride (0.41mL, 3.3mmol), triethylamine (0.59mL, 4.2mmol) and Acetyl Chloride 98Min. (0.3mL, 4.2mmol) reaction, obtain rough 1-[5-chloro-2-(4-trifluoromethyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 77c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(4-trifluoromethyl-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.631.86?C
31H
20Cl
3F
3N
2O
3
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (0.5g, 1.3mmol) and 1-[5-chloro-2-(4-trifluoromethyl-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (3.3mmol) reacts in toluene, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(4-trifluoromethyl-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.22g, 27%)
HRMS (ES
+) m/z is to C
31H
20Cl
3F
3N
2O
3+ H[(M+H)
+] calculated value: 631.0565.Actual measurement: 631.0568.
Embodiment 78a
Preparation intermediate 3-(4-bromo-2-formyl radical-phenoxy group)-benzonitrile
M.W.302.13?C
14H
8BrNO
2
With with in the similar mode of method described in the embodiment 50a, make 5-bromo-2-fluorobenzaldehyde (2.2g, 11mmol) (Alfa) and 3-cyanophenol (1.4g, 12mmol) (Aldrich) and K
2CO
3In N,N-dimethylacetamide, react, obtain 3-(4-bromo-2-formyl radical-phenoxy group)-benzonitrile, be brown solid (yield 3g, 100%).
Embodiment 78b
Preparation intermediate 1-[5-bromo-2-(3-cyano group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.415.37?C
19H
19BrN
2O
2Si
With with in the similar mode of method described in the embodiment 1d, (3g is 10mmol) with 1 to make 3-(4-bromo-2-formyl radical-phenoxy group)-benzonitrile; 1; 1,3,3; 3-hexamethyldisilazane (2.1mL; 10mmol), just-butyllithium (2.5M, 4mL; 10mmol); trimethylsilyl chloride (1.3mL, 10mmol), triethylamine (1.8mL; 13mmol) and Acetyl Chloride 98Min. (0.92mL; 13mmol) reaction obtains rough 1-[5-bromo-2-(3-cyano group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene; be yellow jelly, and without being used for next step with being further purified.
Embodiment 78c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(3-cyano group-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.633.33?C
31H
20BrCl
2N
3O
3
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.55g, 4mmol) with 1-[5-bromo-2-(3-cyano group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (10mmol) reacts in toluene, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(3-cyano group-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.4g, 16%)
HRMS (ES
+) m/z is to C
31H
20BrCl
2N
3O
3+ H[(M+H)
+] calculated value: 632.0138.Actual measurement: 632.0140.
Embodiment 79a
Preparation intermediate 5-bromo-2-[4-(3-hydroxyl-propyl group)-phenoxy group]-phenyl aldehyde
M.W.335.20?C
16H
15BrO
3
With with in the similar mode of method described in the embodiment 50a, make 5-bromo-2-fluorobenzaldehyde (5.5g, 27mmol) (Alfa) and 3-(4-hydroxy phenyl)-1-propyl alcohol (4.5g, 30mmol) (Aldrich) and K
2CO
3In N,N-dimethylacetamide, react, obtain 5-bromo-2-[4-(3-hydroxyl-propyl group)-phenoxy group]-phenyl aldehyde, be brown oil (yield 9g, 99%).
Embodiment 79b
Preparation intermediate 5-bromo-2-{4-[3-(tertiary butyl-dimethyl-silanyloxy base)-propyl group]-phenoxy group }-phenyl aldehyde
M.W.449.46?C
22H
29BrO
3Si
With with in the similar mode of method described in the embodiment 60b, make 5-bromo-2-[4-(3-hydroxyl-propyl group)-phenoxy group]-phenyl aldehyde (9g, 27mmol) with TERT-BUTYL DIMETHYL CHLORO SILANE (4.45g, 30mmol) and imidazoles at N, react in the dinethylformamide, obtain 5-bromo-2-{4-[3-(tertiary butyl-dimethyl-silanyloxy base)-propyl group]-phenoxy group }-phenyl aldehyde, be brown oil (yield 12g, 100%).
Embodiment 79c
Preparation intermediate 1-{5-bromo-2-{4-[3-(tertiary butyl-dimethyl-silanyloxy base)-propyl group]-phenoxy group }-phenyl }-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.562.70?C
27H
40BrNO
3Si
2
With with in the similar mode of method described in the embodiment 1d, make 5-bromo-2-{4-[3-(tertiary butyl-dimethyl-silanyloxy base)-propyl group]-phenoxy group }-phenyl aldehyde (4.72g, 10.5mmol) with 1,1,1,3,3,3-hexamethyldisilazane (2.18mL, 10.5mmol), just-butyllithium (2.5M, 4.2mL, 10.5mmol), trimethylsilyl chloride (1.33mL, 10.5mmol), triethylamine (1.89mL, 13.6mmol) and Acetyl Chloride 98Min. (0.97mL, 13.6mmol) reaction, obtain rough 1-{5-bromo-2-{4-[3-(tertiary butyl-dimethyl-silanyloxy base)-propyl group]-phenoxy group }-phenyl }-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 79d
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[4-(3-hydroxyl-propyl group)-phenoxy group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.666.40?C
33H
27BrCl
2N
2O
4
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.64g, 4.2mmol) and 1-{5-bromo-2-{4-[3-(tertiary butyl-dimethyl-silanyloxy base)-propyl group]-phenoxy group }-phenyl }-3-trimethylsiloxy-2-azepine-1,3-divinyl (10.5mmol) reacts in toluene, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[4-(3-hydroxyl-propyl group)-phenoxy group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.4g, 14%)
HRMS (ES
+) m/z is to C
33H
27BrCl
2N
2O
4+ H[(M+H)
+] calculated value: 665.0604.Actual measurement: 665.0600.
Embodiment 80a
Preparation intermediate 4-(4-chloro-2-formyl radical-phenoxy group)-benzonitrile
M.W.257.68?C
14H
8ClNO
2
With with in the similar mode of method described in the embodiment 50a, make 5-chloro-2-fluoro-phenyl aldehyde (2g, 12.8mmol) (Beta Pharma) and 4-cyanophenol (1.67g, 14mmol) and K
2CO
3In N,N-dimethylacetamide, react, obtain 4-(4-chloro-2-formyl radical-phenoxy group)-benzonitrile, be faint yellow solid (yield 2.81g, 85%).
Embodiment 80b
Preparation intermediate 1-[5-chloro-2-(4-cyano group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.370.91?C
19H
19ClN
2O
2Si
With with in the similar mode of method described in the embodiment 1d, (2.8g is 11mmol) with 1 to make 4-(4-chloro-2-formyl radical-phenoxy group)-benzonitrile; 1; 1,3,3; 3-hexamethyldisilazane (2.3mL; 11mmol), just-butyllithium (2.5M, 4.4mL; 11mmol); trimethylsilyl chloride (1.4mL, 11mmol), triethylamine (2mL; 14mmol) and Acetyl Chloride 98Min. (1mL; 14mmol) reaction obtains rough 1-[5-chloro-2-(4-cyano group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene; be yellow jelly, and without being used for next step with being further purified.
Embodiment 80c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-cyano group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.588.88?C
31H
20Cl
3N
3O
3
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.7g, 4.4mmol) and 1-[5-chloro-2-(4-cyano group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (11mmol) reacts in toluene, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-cyano group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.6g, 23%)
HRMS (ES
+) m/z is to C
31H
20Cl
3N
3O
3+ H[(M+H)
+] calculated value: 588.0643.Actual measurement: 588.0643.
Embodiment 80d
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-cyano group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.588.88?C
31H
20Cl
3N
3O
3
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-cyano group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (500mg) separates two enantiomorphs, and chirality (2 ' R, 3R are provided, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-cyano group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (0.19g, 38%) (RO5254876-000), and chirality (2 ' S, 3S, 4 ' R)-6-chloro-2 '-[5-chloro-2-(4-cyano group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for white solid (0.19g, 38%) (RO5254875-000).
Embodiment 81a
Preparation intermediate 5-chloro-2-(4-methylthio group-phenoxy group)-phenyl aldehyde
M.W.278.76?C
14H
8ClNO
2
With with in the similar mode of method described in the embodiment 50a, make 5-chloro-2-fluoro-phenyl aldehyde (2g, 12.8mmol) (Beta Pharma) and 4-(methylthio group) phenol (1.97g, 14mmol) (Aldrich) and K
2CO
3In N,N-dimethylacetamide, react, obtain 5-chloro-2-(4-methylthio group-phenoxy group)-phenyl aldehyde, be brown oil (yield 3.5g, 98%).
Embodiment 81b
Preparation intermediate 1-[5-chloro-2-(4-methylthio group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.392.00?C
19H
22ClNO
2SSi
With with in the similar mode of method described in the embodiment 1d, (3.5g is 12.6mmol) with 1 to make 5-chloro-2-(4-methylthio group-phenoxy group)-phenyl aldehyde, 1,1,3,3,3-hexamethyldisilazane (2.6mL, 12.6mmol), just-butyllithium (2.5M, 5mL, 12.6mmol), trimethylsilyl chloride (1.6mL, 12.6mmol), triethylamine (2.3mL, 16mmol) and Acetyl Chloride 98Min. (1.2mL, 16mmol) reaction obtains rough 1-[5-chloro-2-(4-methylthio group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 81c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methylthio group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.609.96?C
31H
23Cl
3N
2O
3S
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.96g, 5mmol) with 1-[5-chloro-2-(4-methylthio group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (12.6mmol) reacts in toluene, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methylthio group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.6g, 20%)
HRMS (ES
+) m/z is to C
31H
23Cl
3N
2O
3S+H[(M+H)
+] calculated value: 609.0568.Actual measurement: 609.0568.
Embodiment 82
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methyl sulphonyl-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.641.96?C
31H
23Cl
3N
2O
5S
To racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methylthio group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines] (0.36g is in solution 0.59mmol) for-2,6 ' (1H)-diketone, adding MCPBA (67%, 0.145g, 0.87mmol).Reaction mixture at stirring at room 0.5h, is used saturated Na then
2S
2O
3The aqueous solution and the NaHCO3 aqueous solution wash successively.Separate organic layer, concentrate.Resistates is passed through chromatography (EtOAc: CH
2Cl
2=1: 1) purifying obtains racemize (2 ' R, 3R; 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methyl sulphonyl-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; be faint yellow solid (yield 0.16g, 42%).
HRMS (ES
+) m/z is to C
31H
23Cl
3N
2O
5S+H[(M+H)
+] calculated value: 641.0466.Actual measurement: 641.0464.
Embodiment 83
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methylsulfinyl-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.625.96?C
31H
23Cl
3N
2O
4S
In embodiment 82, pass through chromatography (MeOH: EtOAc=6: 94) purifying; obtain another secondary product racemize (2 ' R; 3R; 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methylsulfinyl-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.07g, 19%).
HRMS (ES
+) m/z is to C
31H
23Cl
3N
2O
4S+H[(M+H)
+] calculated value: 625.0517.Actual measurement: 625.0515.
Embodiment 84a
Preparation intermediate 5-chloro-2-(4-nitro-phenoxy group)-phenyl aldehyde
M.W.277.67?C
13H
8ClNO
4
With with in the similar mode of method described in the embodiment 50a, make 5-chloro-2-fluoro-phenyl aldehyde (1.71g, 10.9mmol) (Beta Pharma) and 4-nitrophenols (1.67g, 12mmol) (Aldrich) and K
2CO
3In N,N-dimethylacetamide, react, obtain 5-chloro-2-(4-nitro-phenoxy group)-phenyl aldehyde, be brown oil (yield 2.23g, 73%).
Embodiment 84b
Preparation intermediate 1-[5-chloro-2-(4-nitro-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.390.90?C
18H
19ClN
2O
4Si
With with in the similar mode of method described in the embodiment 1d, (2.23g is 8mmol) with 1 to make 5-chloro-2-(4-nitro-phenoxy group)-phenyl aldehyde, 1,1,3,3,3-hexamethyldisilazane (1.67mL, 8mmol), just-butyllithium (2.5M, 3.2mL, 8mmol), trimethylsilyl chloride (1.0mL, 8mmol), triethylamine (1.45mL, 10mmol) and Acetyl Chloride 98Min. (0.74mL, 10mmol) reaction obtains rough 1-[5-chloro-2-(4-nitro-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 85c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-nitro-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.608.86?C
30H
20Cl
3N
3O
5
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.25g, 3.2mmol) and 1-[5-chloro-2-(4-nitro-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (8mmol) reacts in toluene, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-nitro-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be faint yellow solid (yield 0.4g, 21%)
HRMS (ES
+) m/z is to C
30H
20Cl
3N
3O
5+ H[(M+H)
+] calculated value: 608.0542.Actual measurement: 608.0543.
Embodiment 86a
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(4-amino-phenoxy group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.578.88?C
30H
22Cl
3N
3O
3
To racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-nitro-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.31g, 0.51mmol) in the solution in dehydrated alcohol (20mL), add Ni (0.6g) and anhydrous hydrazine in Ruan (0.118g, 2.54mmol).Reaction mixture at stirring at room 0.5h, is filtered by the short pad of diatomite then.Filtrate is concentrated.Resistates is distributed between ethyl acetate and water.Separate organic layer, and with water layer ethyl acetate extraction three times.Merge organic layer, water, salt water washing, and MgSO
4Drying and concentrated obtains racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(4-amino-phenoxy group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (yield 0.28g, 95%).
HRMS (ES
+) m/z is to C
30H
22Cl
3N
3O
3+ H[(M+H)
+] calculated value: 578.0800.Actual measurement: 578.0797.
Embodiment 86b
Preparation chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(4-amino-phenoxy group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.578.88?C
30H
22Cl
3N
3O
3
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(4-amino-phenoxy group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (60mg) separates two enantiomorphs, and chirality (2 ' R, 3R are provided, 4 ' S)-2 '-[2-(4-amino-phenoxy group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be pale solid (24mg, 40%) (RO5259489-000), and chirality (2 ' S, 3S, 4 ' R)-2 '-[2-(4-amino-phenoxy group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for pale solid (24mg, 40%) (RO5259490-000).
Embodiment 87
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(4-acetylamino-phenoxy group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.620.92?C
32H
24Cl
3N
3O
4
With with in the similar mode of method described in the embodiment 5b; make the racemize (2 ' S that in embodiment 86a, prepares; 3S; 4 ' R)-2 '-[2-(4-amino-phenoxy group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone (0.18g; 0.32mmol) (28mg 0.352mmol) reacts in tetrahydrofuran (THF) with triethylamine, obtains racemize (2 ' S with Acetyl Chloride 98Min.; 3S; 4 ' R)-2 '-[2-(4-acetylamino-phenoxy group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; be yellow solid (yield 0.13g, 65%).
HRMS (ES
+) m/z is to C
32H
24Cl
3N
3O
4+ H[(M+H)
+] calculated value: 620.0905.Actual measurement: 620.0905.
Embodiment 88a
Preparation intermediate 5-iodo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl aldehyde
M.W.356.17?C
13H
13IN
2O
2
With with in the similar mode of method described in the embodiment 50a, make 2-fluoro-5-benzaldehyde iodine (5.84g, 23.4mmol) (Aldrich) and 1,3,5-trimethylammonium-1H-pyrazoles-4-alcohol (3.24g, 25.7mmol) and K
2CO
3In N,N-dimethylacetamide, react, obtain 5-iodo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl aldehyde, be yellow solid (yield 8.1g, 97%).
1,3,5-trimethylammonium-1H-pyrazoles-4-alcohol is according to by Fagan, and P.J. etc. are at Can.J.Chem.1979, and vol 57, the program preparation described in the 904-912.
Embodiment 88b
Preparation intermediate 1-[5-iodo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.469.40C?
18H
24IN
3O
2Si
With with in the similar mode of method described in the embodiment 1d, with 5-iodo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-(8.1g is 23mmol) with 1,1 for phenyl aldehyde, 1,3,3, the 3-hexamethyldisilazane (4.7mL, 23mmol), just-butyllithium (2.5M, 9.1mL, 23mmol), trimethylsilyl chloride (2.9mL, 23mmol), triethylamine (4.1mL, 30mmol) and Acetyl Chloride 98Min. (2.1mL, 30mmol) reaction, obtain rough 1-[5-iodo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 88c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.687.36?C
30H
25Cl
2IN
4O
3
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (3.5g, 9mmol) with 1-[5-iodo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (23mmol) reacts in toluene, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-and phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be light yellow solid (yield 0.64g, 10%)
HRMS (ES
+) m/z is to C
30H
25Cl
2IN
4O
3+ H[(M+H)
+] calculated value: 687.0421.Actual measurement: 687.0425.
Embodiment 89a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.585.49?C
32H
26Cl
2N
4O
3
With with in the similar mode of method described in the embodiment 6a, with racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.62g, 0.9mmol) with trimethyl silyl acetylene (0.88g, 9mmol), CuI (10mg), triethylamine (2.71g, 27mmol) and dichloro two (triphenylphosphine) palladium (0) (50.5mg, 0.07mmol) at anhydrous N, react in the dinethylformamide, in methyl alcohol, handle then, obtain racemize (2 ' R with the NaOH aqueous solution, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (yield 0.47g, 90%)
HRMS (ES
+) m/z is to C
32H
26Cl
2N
4O
3+ H[(M+H)
+] calculated value: 584.1455.Actual measurement: 584.1457.
Embodiment 89b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.585.49?C
32H
26Cl
2N
4O
3
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.4g) separates two enantiomorphs, and chirality (2 ' R, 3R are provided, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for pale solid (0.18g, 45%) (RO5260375-000), and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for pale solid (0.17g, 44%) (RO5260376-000).
Embodiment 90a
Preparation intermediate 5-bromo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl aldehyde
M.W.309.16?C
13H
13BrN
2O
2
With with in the similar mode of method described in the embodiment 50a, make 5-bromo-2-fluoro-phenyl aldehyde (2g, 10mmol) (Acros) and 1,3,5-trimethylammonium-1H-pyrazoles-4-alcohol (1.3g, 10mmol) and K
2CO
3In N,N-dimethylacetamide, react, obtain 5-bromo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl aldehyde, be white solid (yield 3.1g, 100%).
Embodiment 90b
Preparation intermediate 1-[5-bromo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.422.40?C
18H
24BrN
3O
2Si
With with in the similar mode of method described in the embodiment 1d, with 5-bromo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-(3.1g is 10mmol) with 1,1 for phenyl aldehyde, 1,3,3, the 3-hexamethyldisilazane (1.6g, 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.36g, 13mmol) and Acetyl Chloride 98Min. (1g, 13mmol) reaction, obtain rough 1-[5-bromo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 90c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.640.36?C
30H
25BrCl
2N
4O
3
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.2g, 3mmol) with 1-[5-bromo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (4.2g, 10mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is light yellow solid (yield 0.2g, 10%)
HRMS (ES
+) m/z is to C
30H
25BrCl
2N
4O
3+ H[(M+H)
+] calculated value: 639.0560.Actual measurement: 639.0561.
Embodiment 91a
Preparation intermediate methylsulfonic acid 1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base ester
M.W.236.29?C
9H
16O
5S
With with in the similar mode of method described in the embodiment 32a, make 1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-alcohol (5.1g, 32mmol) (3.7g, 32mmol Aldrich) react in methylene dichloride with triethylamine for (Alfa) and methylsulfonyl chloride, obtain methylsulfonic acid 1, in 4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base ester, be faint yellow oily thing (yield 6.8g, 90%).
Embodiment 91b
Preparation intermediate 5-chloro-2-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base oxygen base)-phenyl aldehyde
M.W.296.75?C
15H
17ClO
4
With with in the similar mode of method described in the embodiment 4a, make the 5-chloro-salicylic aldehyde (2.32g, 14.8mmol) (Aldrich) and methylsulfonic acid 1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base ester (3.5g, 14.8mmol) and K
2CO
3At N, react in the dinethylformamide, obtain 5-chloro-2-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base oxygen base)-phenyl aldehyde, be colorless oil (yield 1.5g, 34%).
Embodiment 91c
Preparation intermediate 1-[5-chloro-2-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.409.99?C
20H
28ClNO
4Si
With with in the similar mode of method described in the embodiment 1d; with 5-chloro-2-(1; 4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base oxygen base)-(1.5g 5mmol) replaces 4-(2-formyl radical-4-iodo-phenoxymethyl)-piperidines-1-t-butyl formate as raw material, with 1 to phenyl aldehyde; 1; 3,3,3-hexamethyldisilazane (0.8g; 5mmol); just-and butyllithium (2.5M, 2mL, 5mmol); trimethylsilyl chloride (.0.55g; 5mmol), and triethylamine (0.7g, 6.8mmol) and Acetyl Chloride 98Min. (0.5g; 6.8mmol) reaction; obtain rough 1-[5-chloro-2-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene; be yellow jelly, and without being used for next step with being further purified.
Embodiment 91d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.627.95?C
32H
29Cl
3N
2O
5
With with in the similar mode of method described in the embodiment 1e, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (0.4g, 1mmol) with 1-[5-chloro-2-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (1.5g, 5mmol) in toluene, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base oxygen base)-and phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be pale solid (yield 0.23g, 37%)
HRMS (ES
+) m/z is to C
32H
29Cl
3N
2O
5+ H[(M+H)
+] calculated value: 627.1215.Actual measurement: 627.1217.
Embodiment 92
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-oxo-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.583.90?C
30H
25Cl
3N
2O
4
To racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base oxygen base)-and phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines] (0.2g is 0.32mmol) in the solution in tetrahydrofuran (THF) (15mL) and water (1mL) for-2,6 ' (1H)-diketone, the adding HCl aqueous solution (2N, 1mL).Reaction mixture at stirring at room 1h, is used NaHCO then
3The aqueous solution is neutralized to " pH " 7.Then with the mixture ethyl acetate extraction.Separate organic layer, use the salt water washing, use MgSO
4Drying and concentrated.Resistates is passed through chromatography (EtOAc: CH
2Cl
2=1: 1) purifying obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-oxo-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.1g, 54%)
HRMS (ES
+) m/z is to C
30H
25Cl
3N
2O
4+ H[(M+H)
+] calculated value: 583.0953.Actual measurement: 583.0953.
Embodiment 93a
Preparation intermediate 2-chloro-6-(4-methoxyl group-phenoxy group)-phenyl aldehyde
M.W.262.69?C
14H
11ClO
3
With with in the similar mode of method described in the embodiment 50a, make 2, the 6-dichlorobenzaldehyde (2.7g, 15mmol) (Aldrich) and 4-methoxyphenol (1.8g, 15mmol) and K
2CO
3In N,N-dimethylacetamide, react, obtain 2-chloro-6-(4-methoxyl group-phenoxy group)-phenyl aldehyde, be yellow oil (yield 3.2g, 80%).
Embodiment 93b
Preparation intermediate 1-[2-chloro-6-(4-methoxyl group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.375.93?C
19H
22ClNO
3Si
With with in the similar mode of method described in the embodiment 1d, (2.8g is 10mmol) with 1 to make 2-chloro-6-(4-methoxyl group-phenoxy group) phenyl aldehyde, 1,1,3,3,3-hexamethyldisilazane (1.6g, 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.36g, 13mmol) and Acetyl Chloride 98Min. (1g, 10mmol) reaction obtains rough 1-[2-chloro-6-(4-methoxyl group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 93c
Preparation racemize (2 ' S, 3R, 4 ' S)-6-chloro-2 '-[2-chloro-6-(4-methoxyl group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.593.89?C
31H
23Cl
3N
2O
4
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (0.56g, 1.4mmol) and 1-[2-chloro-6-(4-methoxyl group-phenoxy group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (10mmol) reacts in toluene, react in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' S, 3R, 4 ' S)-6-chloro-2 '-[2-chloro-6-(4-methoxyl group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be faint yellow solid (yield 0.52g, 60%)
HRMS (ES
+) m/z is to C
31H
23Cl
3N
2O
4+ H[(M+H)
+] calculated value: 593.0796.Actual measurement: 593.0797.
Embodiment 94a
The preparation intermediate trans-4-(tertiary butyl-dimethyl-silanyloxy base)-hexalin
M.W.230.43?C
12H
26O
2Si
To 0 ℃ anti-form-1, the 4-cyclohexanediol (3g, 26mmol) at anhydrous N, in the solution in the dinethylformamide (30mL), add imidazoles (1.7g, 26mmol) and TERT-BUTYL DIMETHYL CHLORO SILANE (3.87g, 26mmol).Then reaction mixture is stirred 1h at 0 ℃.Mixture is distributed between ethyl acetate and water.Separate organic layer, with the water layer ethyl acetate extraction.MgSO is used in the organic layer water and the salt water washing that merge
4Drying and concentrated.Resistates is passed through chromatography (EtOAc: hexane=1; 2) purifying obtains trans-4-(tertiary butyl-dimethyl-silanyloxy base)-hexalin, is white solid (3.9g, 65%).
The raw material anti-form-1, the 4-cyclohexanediol is according to Doyle, M.P. etc. are at Org.Lett.2005, Vol 7, No.22, the program described in the 5035-5038 supplementary material do not change by cis-/anti-form-1,1: 1 mixture of 4-cyclohexanediol is by crystallization preparation.
Embodiment 94b
Preparation intermediate cis-2-[4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-methyl benzoate
M.W.399.01?C
20H
31ClO
4Si
5-chloro-2 hydroxybenzoic acid methyl esters (2.07g to 0 ℃, 11mmol) and diisopropyl azo-2-carboxylic acid (2.98g, 14mmol) in (Aldrich) solution in anhydrous tetrahydro furan (10mL), add trans-4-(tertiary butyl-dimethyl-silanyloxy base)-hexalin (3.2g, 14mmol) and triphenylphosphine (3.64g, 14mmol) mixture in tetrahydrofuran (THF) (40mL).With reaction mixture at stirring at room 18h.Mixture is poured in the water, with ethyl acetate (3x) extraction.Merge organic layer, MgSO is used in water, salt water washing
4Drying and concentrated.Resistates is passed through chromatography (5%EtOAc; Hexane) purifying obtains cis-2-[4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-methyl benzoate, be yellow oil (yield 4.0g, 90%).
Embodiment 94c
Preparation intermediate cis-2-[4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-phenyl aldehyde
M.W.368.98?C
19H
29ClO
3Si
To cis-2-[4-of 0 ℃ (tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-(4g 10mmol) in the solution in anhydrous diethyl ether (30mL), drips LiAlH to 5-chloro-methyl benzoate
4Ether (1M) solution (10mL, 10mmol).Reaction mixture is warming to room temperature and stirs 0.5h.With mixture by dripping water (0.38mL) successively, the NaOH aqueous solution (15%, 0.38mL), and water (1.14mL) and quencher.Mixture is filtered, with ethyl acetate (3x) washing granular sludge.Filtrate is merged, and water, salt water washing separate, and use MgSO
4Drying and concentrated obtains colorless oil (3.6g).This oily matter is dissolved in 1, in the 2-ethylene dichloride, and adds activatory MnO
2(8.34g, 97mmol).Reaction mixture is heated 1h at 80 ℃.With the mixture cool to room temperature, filter by the short pad of diatomite.Filtrate is concentrated, obtains cis-2-[4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-phenyl aldehyde, be yellow solid (yield 3.6g, 97%).
Embodiment 94d
Preparation intermediate 1-[2-[cis-4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.482.22?C
24H
40ClNO
3Si
2
With with in the similar mode of method described in the embodiment 1d, make cis-2-[4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-phenyl aldehyde (3.6g, 9.8mmol) with 1,1,1,3,3,3-hexamethyldisilazane (1.6g, 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.36g, 13mmol) and Acetyl Chloride 98Min. (1g, 13mmol) reaction obtains rough 1-[2-[cis-4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 94d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(cis-4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.585.91?C
30H
27Cl
3N
2O
4
With with in the similar mode of method described in the embodiment 1e, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.52g, 3.8mmol) and 1-[2-[cis-4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (9.8mmol) reacts in toluene, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(cis-4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.4g, 18%)
HRMS (ES
+) m/z is to C
30H
27Cl
3N
2O
4+ H[(M+H)
+] calculated value: 585.1109.Actual measurement: 585.1111.
Embodiment 94e
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(cis-4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.585.91?C
30H
27Cl
3N
2O
4
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(cis-4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (350mg) separates two enantiomorphs, and chirality (2 ' R, 3R are provided, 4 ' S)-6-chloro-2 '-[5-chloro-2-(cis-4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (0.15g, 43%) (RO5256716-000), and chirality (2 ' S, 3S, 4 ' R)-6-chloro-2 '-[5-chloro-2-(cis-4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for white solid (0.15g, 43%) (RO5256713-000).
Embodiment 95a
Preparation intermediate cis-4-(tertiary butyl-dimethyl-silanyloxy base)-hexalin
M.W.230.43?C
12H
26O
2Si
With with in the similar mode of method described in the embodiment 94a, make cis-1,4-cyclohexanediol (3.8g, 33mmol) with TERT-BUTYL DIMETHYL CHLORO SILANE (5g, 34mmol) and imidazoles at N, react in the dinethylformamide, obtain cis-4-(tertiary butyl-dimethyl-silanyloxy base)-hexalin, be colorless oil (2.4g, 31%).
Raw material cis-1,4-cyclohexanediol be not according to changing ground in the program described in the EP218433, by cis-/anti-form-1, mixture preparation in 1: 1 of 4-cyclohexanediol.
Embodiment 95b
The preparation intermediate trans-2-[4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-methyl benzoate
M.W.399.01?C
20H
31ClO
4Si
With with in the similar mode of method described in the embodiment 94b, make cis-4-(tertiary butyl-dimethyl-silanyloxy base)-hexalin (2.7g, 12mmol) with 5-chloro-2 hydroxybenzoic acid methyl esters (1.77g, 9.5mmol) and the diisopropyl azo-2-carboxylic acid, triphenylphosphine reacts in tetrahydrofuran (THF), obtain trans-2-[4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-methyl benzoate, be yellow oil (yield 2.7g, 71%).
Embodiment 95c
The preparation intermediate trans-2-[4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-phenyl aldehyde
M.W.368.98?C
19H
29ClO
3Si
With with in the similar mode of method described in the embodiment 94c, make trans-2-[4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-methyl benzoate (2.7g, 6.76mmol) and LiAlH
4(1M, 6.76mL 6.76mmol) react in ether, use activatory MnO then in methylene dichloride
2(4.64g, 54mmol) oxidation obtain trans-2-[4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-phenyl aldehyde, be white solid (yield 1.12g, 44%).
Embodiment 95d
Preparation intermediate 1-[2-[is trans-4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.482.22?C
24H
40ClNO
3Si
2
With with in the similar mode of method described in the embodiment 1d, make trans-2-[4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-phenyl aldehyde (1.12g, 3mmol) with 1,1,1,3,3,3-hexamethyldisilazane (0.63mL, 3mmol), just-butyllithium (2.5M, 1.2mL, 3mmol), trimethylsilyl chloride (0.39mL, 3mmol), triethylamine (0.55mL, 4mmol) and Acetyl Chloride 98Min. (0.28mL, 4mmol) reaction, obtain rough 1-[2-[trans-4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 95d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(trans-the 4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.585.91?C
30H
27Cl
3N
2O
4
With with in the similar mode of method described in the embodiment 1e, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (0.47g, 1.2mmol) with 1-[2-[trans-4-(tertiary butyl-dimethyl-silanyloxy base)-cyclohexyl oxygen base]-5-chloro-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (3mmol) reacts in toluene, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(cis-4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be light yellow solid (yield 0.3g, 42%)
HRMS (ES
+) m/z is to C
30H
27Cl
3N
2O
4+ H[(M+H)
+] calculated value: 585.1109.Actual measurement: 585.1111.
Embodiment 95e
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(trans-the 4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.585.91?C
30H
27Cl
3N
2O
4
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(trans-the 4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (250mg) separates two enantiomorphs, chirality (2 ' R is provided, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(trans-the 4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be faint yellow solid (88mg, 35%).
Embodiment 96a
Preparation intermediate 5-chloro-4-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl aldehyde
M.W.258.68?C
12H
12ClFO
3
With with in the similar mode of method described in the embodiment 4a, make 5-chloro-4-fluoro-2-phenyl aldehyde (2g, 11.5mmol) with the methylsulfonic acid tetrahydropyran-4-base ester that in embodiment 32a, prepares (3.72g, 17mmol) and K
2CO
3At N, react in the dinethylformamide, obtain 5-chloro-4-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl aldehyde, be yellow solid (yield 1.32g, 44%).
According to Carter, J.S. etc. do not prepare raw material 5-chloro-4-fluoro-2-phenyl aldehyde in the program described in the US6077850 with changing.
Embodiment 96b
Preparation intermediate 1-[5-chloro-4-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.371.92?C
17H
23ClFNO
3Si
With with in the similar mode of method described in the embodiment 1d, (tetrahydrochysene-pyrans-4-base oxygen base)-(1.32g is 5mmol) with 1 for phenyl aldehyde to make 5-chloro-4-fluoro-2-, 1,1,3,3,3-hexamethyldisilazane (0.8g, 10mmol), just-butyllithium (2.5M, 2mL, 5mmol), trimethylsilyl chloride (0.55g, 5mmol), triethylamine (0.7g, 7mmol) and Acetyl Chloride 98Min. (0.5g, 7mmol) reaction obtains rough 1-[5-chloro-4-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 96c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-4-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.589.88?C
29H
24Cl
3FN
2O
4
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 5b, prepares, 3-dihydro-indoles-1-t-butyl formate (0.79g, 2mmol) with 1-[5-chloro-4-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (5mmol) reacts in toluene, handle in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-and 6-chloro-2 '-[5-chloro-4-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.59g, 50%)
HRMS (ES
+) m/z is to C
29H
24Cl
3FN
2O
4+ H[(M+H)
+] calculated value: 589.0859.Actual measurement: 589.0858.
Embodiment 96c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-4-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.589.88?C
29H
24Cl
3FN
2O
4
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-and 6-chloro-2 '-[5-chloro-4-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.3g) separates two enantiomorphs, chirality (2 ' R is provided, 3R, 4 ' S)-and 6-chloro-2 '-[5-chloro-4-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (0.099g, 33%) (RO5259545-000), and chirality (2 ' S, 3S, 4 ' R)-6-chloro-2 '-[5-chloro-4-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for white solid (0.128g, 43%) (RO5259544-000).
Embodiment 97a
Preparation intermediate 5-chloro-4-methyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl aldehyde
M.W.254.72?C
13H
15ClO
3
With with in the similar mode of method described in the embodiment 4a, make 5-chloro-4-methyl-2-phenyl aldehyde (2g, 11.7mmol) (Asta tech) and the methylsulfonic acid tetrahydropyran-4-base ester that in embodiment 32a, prepares (3.8g, 17.6mmol) and K
2CO
3At N, react in the dinethylformamide, obtain 5-chloro-4-methyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl aldehyde, be yellow solid (yield 2g, 67%).
Embodiment 97b
Preparation intermediate 1-[5-chloro-4-methyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.367.95?C
18H
26ClNO
3Si
With with in the similar mode of method described in the embodiment 1d, (tetrahydrochysene-pyrans-4-base oxygen base)-(2g is 7.9mmol) with 1 for phenyl aldehyde to make 5-chloro-4-methyl-2-, 1,1,3,3,3-hexamethyldisilazane (1.6mL, 7.9mmol), just-butyllithium (2.5M, 3.1mL, 7.9mmol), trimethylsilyl chloride (0.99mL, 7.9mmol), triethylamine (1.42mL, 10mmol) and Acetyl Chloride 98Min. (0.73mL, 10mmol) reaction obtains rough 1-[5-chloro-4-methyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 97c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-4-methyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.585.91?C
30H
27Cl
3N
2O
4
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 5b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.22g, 3.14mmol) and 1-[5-chloro-4-methyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (7.8mmol) reacts in toluene, handle in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-and 6-chloro-2 '-[5-chloro-4-methyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.59g, 33%)
HRMS (ES
+) m/z is to C
30H
27Cl
3N
2O
4+ H[(M+H)
+] calculated value: 585.1109.Actual measurement: 585.1109.
Embodiment 98a
Preparation intermediate methylsulfonic acid 2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base ester
M.W.236.33?C
10H
20O
4S
With with in the similar mode of method described in the embodiment 32a, make 2,2,6, (5.5g is 35mmol) with methylsulfonyl chloride (6g for 6-tetramethyl--tetrahydrochysene-pyrans-4-alcohol, 52mmol, Aldrich) and triethylamine in methylene dichloride, react, obtain methylsulfonic acid 2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base ester is yellow oil (yield 8.5g, 100%).
Raw material 2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-alcohol be according to Nemeroff, and N. etc. are at J.Org.Chem.1978, and 43 (2), the program preparation described in the 331-334 is changed slightly.
Embodiment 98b
Preparation intermediate 5-chloro-2-(2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base oxygen base)-phenyl aldehyde
M.W.296.80?C
16H
21ClO
3
With with in the similar mode of method described in the embodiment 4a, make the 5-chloro-salicylic aldehyde (4.6g, 30mmol) (Aldrich) and methylsulfonic acid 2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base ester (8g, 34mmol) and K
2CO
3At N, react in the dinethylformamide, obtain 5-chloro-2-(2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base oxygen base)-phenyl aldehyde, be pale solid (yield 0.94g, 10%).
Embodiment 98c
Preparation intermediate 1-[5-chloro-2-(2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.410.03?C
21H
32ClNO
3Si
With with in the similar mode of method described in the embodiment 1d, make 5-chloro-2-(2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base oxygen base)-(0.94g is 3mmol) with 1 for phenyl aldehyde, 1,1,3,3, the 3-hexamethyldisilazane (0.66mL, 3mmol), just-butyllithium (2.5M, 1.3mL, 3mmol), and trimethylsilyl chloride (.0.4mL, 3mmol), triethylamine (0.57mL, 4mmol) and Acetyl Chloride 98Min. (0.29mL, 4mmol) reaction, obtain rough 1-[5-chloro-2-(2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 98d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.627.99?C
33H
33Cl
3N
2O
4
With with in the similar mode of method described in the embodiment 1e, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 1b, prepares, 3-dihydro-indoles-1-t-butyl formate (0.49g, 1.3mmol) and 1-[5-chloro-2-(2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (3mmol) reacts in toluene, obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (yield 0.3g, 37%)
HRMS (ES
+) m/z is to C
33H
33Cl
3N
2O
4+ H[(M+H)
+] calculated value: 627.1579.Actual measurement: 627.1576.
Embodiment 98e
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.627.99?C
33H
33Cl
3N
2O
4
By chirality SFC, from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.1g) separates two enantiomorphs, and chirality (2 ' R, 3R are provided, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for white solid (33mg, 33%) (RO5260373-000), and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base oxygen base)-and phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, for white solid (33mg, 33%) (RO5260374-000).
Embodiment 99a
Preparation intermediate 5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl aldehyde
M.W.240.69?C
12H
13ClO
3
With with in the similar mode of method described in the embodiment 4a, make the 5-chloro-salicylic aldehyde (6g, 39mmol) (Aldrich) and the methylsulfonic acid tetrahydropyran-4-base ester that in embodiment 32a, prepares (10g, 46mmol) and K
2CO
3At N, react in the dinethylformamide, obtain 5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl aldehyde, be yellow solid (yield 2g, 64%).
Embodiment 99b
Preparation intermediate 1-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.353.92?C
17H
24ClNO
3Si
With with in the similar mode of method described in the embodiment 1d, (tetrahydrochysene-pyrans-4-base oxygen base)-(2g is 8.3mmol) with 1 for phenyl aldehyde to make 5-chloro-2-, 1,1,3,3,3-hexamethyldisilazane (1.7mL, 8.3mmol), just-butyllithium (2.5M, 3.3mL, 8.3mmol), trimethylsilyl chloride (1.06mL, 8.3mmol), triethylamine (1.5mL, 11mmol) and Acetyl Chloride 98Min. (0.77mL, 11mmol) reaction obtains rough 1-[5-chloro-4-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene, be yellow jelly, and without being used for next step with being further purified.
Embodiment 99c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.571.89?C
29H
25Cl
3N
2O
4
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 that in embodiment 5b, prepares, 3-dihydro-indoles-1-t-butyl formate (1.3g, 3.3mmol) and 1-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (8.3mmol) reacts in toluene, handle in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' S)-and 6-chloro-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 1.2g, 64%)
HRMS (ES
+) m/z is to C
29H
25Cl
3N
2O
4+ H[(M+H)
+] calculated value: 571.0953.Actual measurement: 571.0951.
Embodiment 100a
Preparation intermediate E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-t-butyl formate
M.W.408.26?C
20H
16Cl
2FNO
3
With with the similar mode of method described in embodiment 1a and the embodiment 1b, make 3-chloro-2-fluorobenzaldehyde (3.1g, 20mmol) with 6-chlorine oxindole (3.3g, 20mmol) in methyl alcohol, react with tetramethyleneimine, then with dimethyl dicarbonate butyl ester (6.5g, 30mmol) (Aldrich), triethylamine and 4-dimethylaminopyridine react in methylene dichloride, obtain E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-t-butyl formate, be yellow solid (yield: 6.1g, 75%).
Embodiment 100b
Preparation racemize (2 ' R, 3R, 4 ' R)-6-chloro-4 '-(3-chloro-2-fluoro-phenyl)-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.589.88?C
29H
24Cl
3FN
2O
4
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-t-butyl formate (0.68g, 1.66mmol) and 1-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (4mmol) reacts in toluene, handle in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' R)-and 6-chloro-4 '-(3-chloro-2-fluoro-phenyl)-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.12g, 12%)
HRMS (ES
+) m/z is to C
29H
24Cl
3FN
2O
4+ H[(M+H)
+] calculated value: 589.0859.Actual measurement: 589.0856.
Embodiment 101a
Preparation intermediate E/Z-6-chloro-3-(3-chloro-4-fluoro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-t-butyl formate
M.W.408.26?C
20H
16Cl
2FNO
3
With with the similar mode of method described in embodiment 1a and the embodiment 1b, make 3-chloro-4-fluorobenzaldehyde (3.5g, 23mmol) with 6-chlorine oxindole (4.7g, 28mmol) in methyl alcohol, react with tetramethyleneimine, then with dimethyl dicarbonate butyl ester (5g, 23mmol) (Aldrich), triethylamine and 4-dimethylaminopyridine react in methylene dichloride, obtain E/Z-6-chloro-3-(3-chloro-4-fluoro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-t-butyl formate, be yellow solid (yield: 4.5g, 48%).
Embodiment 101b
Preparation racemize (2 ' R, 3R, 4 ' R)-6-chloro-4 '-(3-chloro-4-fluoro-phenyl)-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.589.88?C
29H
24Cl
3FN
2O
4
With with in the similar mode of method described in the embodiment 32d, make E/Z-6-chloro-3-(3-chloro-4-fluoro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-t-butyl formate (0.68g, 1.66mmol) and 1-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (4mmol) reacts in toluene, handle in methylene dichloride with trifluoroacetic acid then, obtain racemize (2 ' R, 3R, 4 ' R)-and 6-chloro-4 '-(3-chloro-4-fluoro-phenyl)-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.14g, 14%)
HRMS (ES
+) m/z is to C
29H
24Cl
3FN
2O
4+ H[(M+H)
+] calculated value: 589.0859.Actual measurement: 589.0856.
Embodiment 102a
Preparation intermediate 2-(4-bromo-2-formyl radical-phenoxy group)-2-methyl-ethyl propionate
M.W.315.17?C
13H
15BrO
4
To 5-bromo-2-hydroxyl-phenyl aldehyde (14g, 70mmol), KI (5g) and K
2CO
3(19g, 140mmol) in the mixture in DMF (100mL), adding 2-bromo-2-methyl-ethyl propionate (17.6g, 90mmol).At 140 ℃ of heating 2h, cool to room temperature distributes between water and ethyl acetate then with mixture.Organic layer is washed with water, use anhydrous Na
2SO
4Dry and concentrated.Resistates by the column chromatography purifying, is obtained title compound (15g).
Embodiment 102b
Preparation intermediate 1-[5-bromo-2-(1-ethoxy carbonyl-1-methyl-oxyethyl group)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.428.40?C
18H
26BrNO
4Si
To 0 ℃ 2-(4-bromo-2-formyl radical-phenoxy group)-2-methyl-ethyl propionate (6g, 19mmol) in the mixture in THF (80mL), add the solution of two (trimethyl silyl) Lithamide in THF (1M, 19mL, 19mmol).Mixture is stirred 1h in 0 ℃ under argon gas.Drip then trimethylsilyl chloride (2.4mL, 19mmol), follow disposable adding triethylamine (3.44mL, 24.6mmol) and dripping acetyl chloride (1.75mL, 24.6mmol) solution in diethyl ether (80mL).Remove cooling bath, and with mixture at stirring at room 1h.Under argon gas, mixture is filtered on diatomite fast, and filtrate is under reduced pressure concentrated.Resistates is dissolved in the toluene (19mL), obtains the solution (1M) of title compound.
Embodiment 102c
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-ethoxy carbonyl-1-methyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.646.37?C
30H
27BrCl
2N
2O
5
To 1-[5-bromo-2-(1-ethoxy carbonyl-1-methyl-oxyethyl group)-phenyl]-3-trimethylsiloxy-2-azepine-1, toluene solution (the 1M of 3-divinyl, 12mL, add E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(t-butyl formate)-1 12mmol), the 3-dihydro-indol-2-one (1.5g, 3.8mmol).Use microwave in 135 ℃ of irradiation 40min reaction mixture, by the column chromatography purifying, obtain title compound then, be white solid (800mg).
Embodiment 102d
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-hydroxycarbonyl group-1-methyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.618.32?C
28H
23BrCl
2N
2O
5
To racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-ethoxy carbonyl-1-methyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (700mg, 1.08mmol) in the mixture in methyl alcohol (20mL), add NaOH (120mg, 3mmol) solution in water (10mL).At 60 ℃ of heating 1.5h, evaporation to be removing methyl alcohol with mixture, cool to room temperature, and arrive " pH " 2 with the HCl acidified aqueous solution.Throw out is collected, washed with water and drying, obtain title compound, be white solid (610mg).
Embodiment 102e
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[2-(4-ethanoyl-piperazine-1-yl)-1,1-dimethyl-2-oxo-oxyethyl group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.728.468?C
34H
33BrCl
2N
4O
5
To racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-hydroxycarbonyl group-1-methyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (40mg, 0.065mmol), EDCI (18.7mg, 0.098mmol), HOBt (15mg, 0.098mmol) and DIPEA (25mg is 0.2mmol) in the mixture in THF (2mL), adding 1-piperazine-1-base-ethyl ketone (25mg, 0.195mmol).Mixture in stirred overnight at room temperature, by the preparation HPLC purifying, is obtained title compound, be white solid (11mg).
m/z(M+H)
+：727
Embodiment 103
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[2-(4,4-two fluoro-piperidines-1-yl)-1,1-dimethyl-2-oxo-oxyethyl group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.721.423?C
33H
30BrCl
2F
2N
3O
4
To racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-hydroxycarbonyl group-1-methyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (40mg, 0.065mmol), EDCI (18.7mg, 0.098mmol), HOBt (15mg, 0.098mmol) and DIPEA (75mg 0.6mmol) adds 4 in the mixture in THF (2mL), 4-difluoro piperidine hydrochlorate (30mg, 0.195mmol).Mixture in stirred overnight at room temperature, by the preparation HPLC purifying, is obtained title compound, be white solid (19mg).
m/z(M+H)
+：720
Embodiment 104
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[1-methyl isophthalic acid-(2,2,2-three fluoro-ethylamino formyl radicals)-oxyethyl group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.699.349?C
30H
2BrCl
2F
3N
3O
4
To racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-hydroxycarbonyl group-1-methyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines] and-2,6 ' (1H)-diketone (40mg, 0.065mmol), EDCI (18.7mg, 0.098mmol), HOBt (15mg, 0.098mmol) and DIPEA (75mg, 0.6mmol) add 2 in the mixture in THF (2mL), 2, and 2-trifluoroethyl amine hydrochlorate (25mg, 0.185mmol).Mixture in stirred overnight at room temperature, by the preparation HPLC purifying, is obtained title compound, be white solid (19mg).
m/z(M+H)
+：698
Embodiment 105
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-formyl-dimethylamino-1-methyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.645.378?C
30H
28BrCl
2N
3O
4
To racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-hydroxycarbonyl group-1-methyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (40mg, 0.065mmol), EDCI (18.7mg, 0.098mmol), HOBt (15mg, 0.098mmol) and DIPEA (75mg, 0.6mmol) add in the mixture in THF (2mL) the dimethyl amine hydrochloride (20mg, 0.25mmol).Mixture in stirred overnight at room temperature, by the preparation HPLC purifying, is obtained title compound, be white solid (26mg).
m/z(M+H)
+：644
Embodiment 106a
Preparation intermediate 2,2-dimethyl-3-(toluene-4-alkylsulfonyl oxygen base)-methyl propionate
M.W.286.35?C
13H
18O
5S
To 3-hydroxyl-2, and 2-dimethyl-methyl propionate (13.2g, 0.1mol), K
2CO
3(20g, 0.14mol) and DMAP (6.2g, 0.05mol) add in the mixture in DCM (100mL) p-toluenesulfonyl chloride (19g, 0.1mol).Mixture in stirred overnight at room temperature, is filtered then.Filtrate with the HCl aqueous solution (1M) and water washing, is used anhydrous Na
2SO
4Dry and concentrated, obtain title compound (15g).
Embodiment 106b
Preparation intermediate 3-(4-bromo-2-formyl radical-phenoxy group)-2,2-dimethyl-methyl propionate
M.W.315.17?C
13H
15BrO
4
To 5-bromo-2-hydroxyl-phenyl aldehyde (4g, 20mmol), KI (1g) and K
2CO
3(4g 29mmol) in the mixture in DMF (10mL), adds 2, and 2-dimethyl-3-(toluene-4-alkylsulfonyl oxygen base)-methyl propionate (6.9g, 24mmol).At 140 ℃ of heating 2h, cool to room temperature distributes between water and ethyl acetate then with mixture.Water (3x) washing organic layer is used anhydrous Na
2SO
4Dry and concentrated.Resistates by the column chromatography purifying, is obtained title compound (5.4g).
Embodiment 106c
Preparation intermediate 1-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy-) phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.428.4?C
18H
26BrNO
4Si
To 0 ℃ 3-(4-bromo-2-formyl radical-phenoxy group)-2,2-dimethyl-methyl propionate (5g, 16mmol) add in the mixture in THF (80mL) two (trimethyl silyl) Lithamide THF solution (1M, 16mL, 16mmol).With mixture under the uniform temp, under argon gas, stir 1.5h.Drip then trimethylsilyl chloride (2mL, 16mmol), follow disposable adding triethylamine (2.87mL, 20.8mmol) and dripping acetyl chloride (1.46mL, 20.8mmol) solution in diethyl ether (80mL).Remove cooling bath, and with mixture at stirring at room 1h.Mixture is filtered on diatomite under nitrogen fast, and filtrate is under reduced pressure concentrated.Resistates is dissolved in the toluene (16mL), obtains the solution (1M) of title compound.
Embodiment 106d
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy-)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.646.37?C
30H
27BrCl
2N
2O
5
To 1-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy-) phenyl]-3-trimethylsiloxy-2-azepine-1, toluene solution (the 1M of 3-divinyl, 12mL, add E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(t-butyl formate)-1 12mmol), the 3-dihydro-indol-2-one (1.5g, 3.8mmol).Use microwave in 135 ℃ of irradiation 40min reaction mixture, by the column chromatography purifying, obtain title compound then, be white solid (300mg).
Embodiment 106e
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-hydroxycarbonyl group-2-methyl-propoxy-)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.632.34?C
29H
25BrCl
2N
2O
5
To racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy-)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-] indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (106mg, 0.16mmol) in the mixture in methyl alcohol (6mL), add NaOH (30mg, 0.75mmol) solution in water (3mL).At 60 ℃ of heating 5h, evaporation to be removing methyl alcohol with mixture, cool to room temperature, and arrive " pH " 2 with the HCl acidified aqueous solution.Throw out is collected and drying, obtained title compound, be white solid (70mg).m/z(M+H)
+：617
Embodiment 106f
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-formyl-dimethylamino-2-methyl-propoxy-)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.659.405?C
31H
30BrCl
2N
3O
4
To racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-hydroxycarbonyl group-2-methyl-propoxy-)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (50mg, 0.08mmol), EDCI (23mg, 0.12mmol), HOBt (18.4mg, 0.12mmol) and DIPEA (62mg is 0.48mmol) in the mixture in THF (2mL), adding dimethyl amine hydrochloride (20mg, 0.25mmol).Mixture in stirred overnight at room temperature, by the preparation HPLC purifying, is obtained title compound, be white solid (20mg).
m/z(M+H)
+：658
Embodiment 107
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2,2-dimethyl-3-oxo-3-tetramethyleneimine-1-base-propoxy-)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.685.443?C
33H
32BrCl
2N
3O
4
To racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-hydroxycarbonyl group-2-methyl-propoxy-)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (50mg, 0.08mmol), EDCI (23mg, 0.12mmol), HOBt (18.4mg, 0.12mmol) and DIPEA (62mg is 0.48mmol) in the mixture in THF (2mL), the adding tetramethyleneimine (17mg, 0.24mmol).Mixture in stirred overnight at room temperature, by the preparation HPLC purifying, is obtained title compound, be white solid (33mg).
m/z(M+H)
+：684
Embodiment 108a
Preparation intermediate toluene-4-sulfonic acid 3-methyl-trimethylene oxide-3-base methyl esters
M.W.256.32?C
12H
16O
4S
To (3-methyl-trimethylene oxide-3-yl)-methyl alcohol (10.2g, 0.1mol) and DMAP (18.3g, 0.15mol) in the mixture in DCM (100mL), add 4-methyl-benzene sulfonyl chloride (19g, 0.1mol).Mixture at stirring at room 1h, is filtered then.Filtrate with the HCl aqueous solution (1M) and water washing, is used anhydrous Na
2SO
4Dry and concentrated, obtain title compound (18g).
Embodiment 108b
Preparation intermediate 5-bromo-2-(3-methyl-trimethylene oxide-3-ylmethoxy)-phenyl aldehyde
M.W.285.14?C
12H
13BrO
3
To 5-bromo-2-hydroxyl-phenyl aldehyde (14g, 70mmol), KI (5g) and K
2CO
3(19g, 140mmol) in the mixture in DMF (100mL), adding toluene-4-sulfonic acid 3-methyl-trimethylene oxide-3-base methyl esters (18g, 70mmol).At 140 ℃ of heating 2h, cool to room temperature distributes between water and ethyl acetate then with mixture.Organic layer is washed with water 3 times, use anhydrous Na
2SO
4Dry and concentrated.Resistates by the column chromatography purifying, is obtained title compound (10g).
Embodiment 108c
Preparation intermediate 1-[5-bromo-2-(3-methyl-trimethylene oxide-3-ylmethoxy) phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.398.38?C
17H
24BrNO
3Si
To 0 ℃ 5-bromo-2-(3-methyl-trimethylene oxide-3-ylmethoxy)-phenyl aldehyde (4.5g, 16mmol) in the mixture in THF (80mL), add two (trimethyl silyl) Lithamide THF solution (1M, 16mL, 16mmol).Under argon gas, mixture is stirred 1h under uniform temp.Drip then trimethylsilyl chloride (2mL, 16mmol) (Aldrich), follow disposable adding triethylamine (2.87mL, 20.9mmol) and dripping acetyl chloride (1.46mL, 20.9mmol) solution in diethyl ether (80mL).Remove cooling bath, and with mixture at stirring at room 1h.Mixture is filtered on diatomite under nitrogen fast, and filtrate is under reduced pressure concentrated.Resistates is dissolved in the toluene (16mL), obtains the solution (1M) of title compound.
Embodiment 108d
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(3-methyl-trimethylene oxide-3-ylmethoxy)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.616.337?C
29H
25BrCl
2N
2O
4
To 1-[5-bromo-2-(3-methyl-trimethylene oxide-3-ylmethoxy) phenyl]-3-trimethylsiloxy-2-azepine-1, toluene solution (the 1M of 3-divinyl, 12mL, add E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(t-butyl formate)-1 12mmol), the 3-dihydro-indol-2-one (1.5g, 3.8mmol).Use microwave in 135 ℃ of irradiation 40min reaction mixture, by the column chromatography purifying, obtain title compound then, be white solid (300mg).
m/z(M+H)
+：616
Embodiment 108e
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-bromo-2-(3-methyl-trimethylene oxide-3-ylmethoxy) phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.616.337?C
29H
25BrCl
2N
2O
4
Use the chirality preparation HPLC, from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-bromo-2-(3-methyl-trimethylene oxide-3-ylmethoxy) phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (RO5220487-000) (40mg) separates two enantiomorphs, chirality (2 ' R is provided, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-bromo-2-(3-methyl-trimethylene oxide-3-ylmethoxy) phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (15mg) (RO5247601-000) and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-bromo-2-(3-methyl-trimethylene oxide-3-ylmethoxy) phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (15mg) is (RO5247602-000).
Embodiment 109a
Preparation intermediate 5-bromo-2-(4-fluoro-benzyloxy)-phenyl aldehyde
M.W.309.14?C
14H
10BrFO
2
To 5-bromo-2-hydroxyl-phenyl aldehyde (5g, 25mmol), KI (2g) and K
2CO
3(7g, 50mmol) in the mixture in DMF (100mL), adding 1-chloromethyl-4-fluoro-benzene (3.96g, 28mmol).At 140 ℃ of heating 2h, cool to room temperature distributes between water and ethyl acetate then with mixture.Organic layer is washed with water 3 times, use anhydrous Na
2SO
4Dry and concentrated.Resistates by the column chromatography purifying, is obtained title compound (4.5g).
Embodiment 109b
Preparation 1-[5-bromo-2-(4-fluoro-benzyloxy) phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.422.37?C
19H
21BrFNO
2Si
To 0 ℃ 5-bromo-2-(4-fluoro-benzyloxy)-phenyl aldehyde (4.4g, 14mmol) in the mixture in THF (60mL), add two (trimethyl silyl) Lithamide THF solution (1M, 14mL, 14mmol).Under argon gas, mixture is stirred 1h under uniform temp.Drip then trimethylsilyl chloride (1.75mL, 14mmol), follow disposable adding triethylamine (2.51mL, 18mmol) and dripping acetyl chloride (1.28mL, 18mmol) solution in diethyl ether (60mL).Remove cooling bath, and with mixture at stirring at room 1h.Mixture is filtered on diatomite under nitrogen fast, and filtrate is under reduced pressure concentrated.Resistates is dissolved in the toluene (14mL), obtains the solution (1M) of title compound.
Embodiment 109c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-fluoro-benzyloxy)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.640.334?C
31H
22BrCl
2FN
2O
3
To 1-[5-bromo-2-(4-fluoro-benzyloxy) phenyl]-3-trimethylsiloxy-2-azepine-1, the toluene solution of 3-divinyl (1M, 12mL, 12mmol) middle E/Z-6-chloro-3-(3-chloro-the benzylidene)-1-(t-butyl formate)-1 that adds, the 3-dihydro-indol-2-one (1.5g, 3.8mmol).Use microwave in 135 ℃ of irradiation 40min reaction mixture, by the column chromatography purifying, obtain title compound then, be white solid (160mg).
m/z(M+H)
+：639
Embodiment 110a
Preparation intermediate toluene-4-sulfonic acid 3-ethyl-trimethylene oxide-3-base methyl esters
M.W.270.35?C
13H
18O
4S
To (3-ethyl-trimethylene oxide-3-yl)-methyl alcohol (11.6g, 0.1mol) and DMAP (18.3g, 0.15mol) in the mixture in DCM (100mL), add 4-methyl-benzene sulfonyl chloride (19g, 0.1mol).Mixture at stirring at room 1h, is filtered then.Filtrate is used the HCl aqueous solution (1M) and water washing, anhydrous Na
2SO
4Dry and concentrated, obtain title compound (19g).
Embodiment 110b
Preparation intermediate 5-bromo-2-(3-ethyl-trimethylene oxide-3-ylmethoxy)-phenyl aldehyde
M.W.299.17?C
13H
15BrO
3
To 5-bromo-2-hydroxyl-phenyl aldehyde (14g, 70mmol), KI (5g) and K
2CO
3(19g, 140mmol) in the mixture in DMF (100mL), adding toluene-4-sulfonic acid 3-ethyl-trimethylene oxide-3-base methyl esters (19g, 70mmol).At 140 ℃ of heating 2h, cool to room temperature distributes between water and ethyl acetate then with mixture.Organic layer is washed with water 3 times, use anhydrous Na
2SO
4Dry and concentrated.Resistates by the column chromatography purifying, is obtained title compound (10g).
Embodiment 110c
Preparation intermediate 1-[5-bromo-2-(3-ethyl-trimethylene oxide-3-ylmethoxy) phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.412.40?C
18H
26BrNO
3Si
To 0 ℃ 5-bromo-2-(3-ethyl-trimethylene oxide-3-ylmethoxy)-phenyl aldehyde (5.9g, 20mmol) in the mixture in THF (80mL), add two (trimethyl silyl) Lithamide THF solution (1M, 20mL, 20mmol).Under argon gas, mixture is stirred 1h under uniform temp.Drip then trimethylsilyl chloride (2.5mL, 20mmol) (Aldrich), follow disposable adding triethylamine (3.6mL, 26mmol) and dripping acetyl chloride (1.83mL, 26mmol) solution in diethyl ether (80mL).Remove cooling bath, and with mixture at stirring at room 1h.Mixture is filtered on diatomite under nitrogen fast, and filtrate is under reduced pressure concentrated.Resistates is dissolved in the toluene (20mL), obtains the solution (1M) of title compound.
Embodiment 110d
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(3-ethyl-trimethylene oxide-3-ylmethoxy)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.630.363?C
30H
27BrCl
2N
2O
4
To 1-[5-bromo-2-(3-ethyl-trimethylene oxide-3-ylmethoxy) phenyl]-3-trimethylsiloxy-2-azepine-1, toluene solution (the 1M of 3-divinyl, 12mL, add E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(t-butyl formate)-1 12mmol), the 3-dihydro-indol-2-one (1.5g, 3.8mmol).Use microwave in 135 ℃ of irradiation 40min reaction mixture, by the column chromatography purifying, obtain title compound then, be white solid (200mg).
m/z(M+H)
+：629.
Embodiment 111a
Preparation intermediate 4-methylsulfonyl oxygen base-piperidines-1-t-butyl formate
M.W.279.36?C
11H
21NO
5S
At 0 ℃, to 4-hydroxy-piperdine-1-t-butyl formate (4g, 20.20mmol) and DMAP (3g, 24mmol) add in the solution in DCM (50mL) methylsulfonyl chloride (2.7g, 24mmol).After stirring 2h, mixture is filtered.Filtrate is used 0.5N HCl (50mL), Na
2CO
3The aqueous solution (1M, 50mL) and salt solution (50mL) washing, anhydrous Na
2SO
4Drying and concentrated obtains title compound, is yellow solid (5g).
Embodiment 111b
Preparation intermediate 4-(2-formyl radical-4-trifluoromethyl-phenoxy group)-piperidines-1-t-butyl formate
M.W.373.38?C
18H
22F
3NO
4
With 2-hydroxyl-5-trifluoromethyl-phenyl aldehyde (1.36g, 7.17mmol), 4-methylsulfonyl oxygen base-piperidines-1-t-butyl formate (2.2g, 7.88mmol) and K
2CO
3(2.96g, 21.5mmol) at anhydrous N, the mixture in the dinethylformamide (15mL) is at 100 ℃ of heating 1h.Behind cool to room temperature, mixture is filtered and filtrate is concentrated.Resistates is dissolved among the DCM (50mL).With solution with water washing, anhydrous Na
2SO
4Dry and concentrated.Resistates by chromatography purification, is obtained title compound (1.43g).
Embodiment 111c
Preparation intermediate 1-[2-(1-tertbutyloxycarbonyl-piperidin-4-yl oxygen base)]-5-trifluoromethyl-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.486.61?C
23H
33F
3N
2O
4Si
Under argon gas, in room temperature in anhydrous tetrahydro furan (10mL), add LiHMDS (3.8mmol, in the THF solution (1M) 3.8mL), then add 4-(2-formyl radical-4-trifluoromethyl-phenoxy group)-piperidines-1-t-butyl formate (1.43g, 3.83mmol).With mixture behind stirring at room 0.5h, drip trimethylsilyl chloride (0.48mL, 3.8mmol).On the cooling ice bath, the temperature of mixture is reduced to 0 ℃ then.(0.71ml 4.87mmol), follows dripping acetyl chloride (0.36ml, 4.87mmol) solution in diethyl ether (20ml) to disposable adding triethylamine in this mixture.Remove cooling bath, and with mixture in stirred overnight at room temperature.Mixture is filtered on diatomite under nitrogen fast, and filtrate is under reduced pressure concentrated, obtain title compound, be yellow jelly, and without being used for next step with being further purified.
Embodiment 111d
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-tertbutyloxycarbonyl-piperidin-4-yl oxygen base)]-5-trifluoromethyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.704.58?C
35H
34Cl
2F
3N
3O
5
To 1-[2-(1-tertbutyloxycarbonyl-piperidin-4-yl oxygen base)]-5-trifluoromethyl-phenyl]-3-trimethylsiloxy-2-azepine-1,3-divinyl (2.6g, 5.4mmol) in the solution in toluene (5.4mL), add E/Z-6-chloro-3-(3-chloro-benzylidene)-1-t-butyl formate-1, the 3-dihydro-indol-2-one (300mg, 0.77mmol).Mixture is heated 30min by microwave exposure in 130 ℃ under argon gas.Behind cool to room temperature, mixture concentrated and with resistates by quick column purification, obtain title compound (10mg).
m/z(M+H)
+：704
Embodiment 112a
Preparation intermediate 5-bromo-2-iodo-phenyl aldehyde
M.W.310.92?C
7H
4BrIO
In 0 ℃ to 5-bromo-2-iodo-benzonitrile (1.54g, 5mmol) drip in the solution in DCM (15mL) DIBALH solution (6mL, 6mmol).After adding, reaction mixture is warming to r.t. and stirs 2h.Then mixture is poured among the 1N HCl of the ice of 20g and 20mL, filtered and, wash, use MgSO with sodium bicarbonate aqueous solution with DCM (40mL) extraction
4Dry and concentrated, obtain raw product (yield: 1.2g).
Embodiment 112b
Preparation intermediate 1-(2-iodo-5-bromo-phenyl)-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.424.15?C
12H
15BrIOSi
Under argon gas, in room temperature in anhydrous tetrahydro furan (120mL), add LiHMDS THF solution (42mmol, 42ml), then add 5-bromo-2-iodo-phenyl aldehyde (13g, 42mmol).With mixture behind stirring at room 0.5h, drip trimethylsilyl chloride (5.32mL, 42mmol).On the cooling ice bath, the temperature of mixture is cooled to 0 ℃ then.(7.6mL 54.4mmol), follows dripping acetyl chloride (3.9mL, 54.4mmol) solution in diethyl ether (200mL) to disposable adding triethylamine in this mixture.Remove cooling bath, and with mixture at stirring at room 1h.Mixture is filtered on diatomite under nitrogen fast, and filtrate is under reduced pressure concentrated, obtain title compound, be yellow jelly, and without being used for next step with being further purified.
Embodiment 112c
Preparation intermediate racemize (2 ' S, 3R, 4 ' S)-2 '-(5-bromo-2-iodo-phenyl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.642.12?C
24H
16BrCl
2N
2O
2
With with in the similar mode of method described in the 32d, make E/Z-6-chloro-3-(3-chloro-benzylidene)-1-t-butyl formate-1,3-dihydro-indol-2-one (3.9g, 8mmol) with 1-(5-bromo-2-iodine)-3-trimethylsiloxy-2-azepine-1,3-divinyl (21mmol) reacts in toluene, obtain title compound, be white solid (yield: 600mg).
Embodiment 112d
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-methyl-piperidin-4-yl amino)-phenyl]-6-chloro-4 '-(5-chloro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.628.40?C
30H
29Cl
2N
4O
2
To racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-bromo-2-iodo-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2, (32mg 0.05mmol) in the solution in DMF (5mL), adds 1-methyl-piperidin-4-yl amine (8mg g to 6 ' (1H)-diketone under argon gas, 0.075mmol), Cs
2CO
3(33mg, 0.01mmol), 2-ethanoyl-pimelinketone (1.4mg) and CuI (1mg).Mixture is stirred 5h at r.t., between ethyl acetate and water, distribute then.Separate organic layer, and with the water layer ethyl acetate extraction.With the organic layer NaHCO that merges
3Solution washing, MgSO
4Dry and concentrated.With resistates preparation HPLC purifying, obtain title compound, be white solid (yield: 10mg).
m/z(M+H)
+：627
Embodiment 113a
Preparation intermediate 2-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-5-iodo-phenyl aldehyde
M.W.406.34?C
15H
23IO
3Si
(6.68g, 26.9mmol) (Aldrich) in the solution in the dinethylformamide (150mL), adds anhydrous K at N to 5-iodine salicylic aldehyde
2CO
3(11.17g, 80.7mmol) and (2-bromo-the oxyethyl group)-tertiary butyl-dimethyl-silane (7.74g, 32.3mmol, Aldrich).Reaction mixture is heated 18h at 65 ℃.With thick product cool to room temperature, with ethyl acetate dilution, water, salt water washing.Separate organic layer, MgSO
4Drying concentrates, and obtains 2-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-5-iodo-phenyl aldehyde, be yellow oil (yield 10g, 100%).
Embodiment 113b
Preparation intermediate 1-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
M.W.519.58?C
20H
34lNO
3Si
2
Under nitrogen in room temperature to 1,1,1,3,3, (4.36mL 21mmol) is just adding in (Aldrich)-butyllithium (2.5M, 8.4mL, 21mmol) (Aldrich) the 3-hexamethyldisilazane.With reaction mixture stirring at room 10 minutes.Add anhydrous tetrahydro furan (60mL) then, then add 2-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-5-iodo-phenyl aldehyde (8.53g, 21mmol).Mixture behind stirring at room 0.5h, is dripped trimethylsilyl chloride (2.66mL, 21mmol) (Aldrich).On the cooling ice bath, the temperature of mixture is cooled to 0 ℃ then.(3.8mL 27.2mmol), follows dripping acetyl chloride (1.94mL, 27.2mmol) solution in diethyl ether (100mL) to disposable adding triethylamine in this mixture.Remove cooling bath, and with mixture at stirring at room 1h.Mixture is filtered on diatomite under nitrogen fast, and filtrate is under reduced pressure concentrated, obtain rough 1-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1, the 3-divinyl, be yellow oil, and without being used for next step with being further purified.
Embodiment 113c
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.623.28?C
26H
21Cl
2IN
2O
4
To 1-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-5-iodo-phenyl]-3-trimethylsiloxy-2-azepine-1, in the solution of 3-divinyl (21mmol) in toluene (30mL), be added in E/Z-6-chloro-3-(3-chlorine the benzylidene)-2-oxo-2 for preparing among the embodiment 1b, 3-dihydro-indoles-1-t-butyl formate (1.2g, 3.1mmol).Reaction mixture is stirred 45min in 140 ℃ under nitrogen, in sealed tube.Behind the solution cool to room temperature, reaction mixture is concentrated.Be dissolved in resistates in the methylene dichloride (20mL) and adding trifluoroacetic acid (20mL).With reaction mixture behind stirring at room 4h, mixture is concentrated.With resistates at saturated NaHCO
3Distribute between solution and the ethyl acetate.With the water layer ethyl acetate extraction.With the organic layer Na that merges
2SO
4Dry and concentrated.Resistates is passed through chromatography (EtOAc: CH
2Cl
2=1: 3) purifying obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be faint yellow solid (yield 0.46g, 25%).
HRMS (ES
+) m/z is to C
26H
21Cl
2IN
2O
4+ H[(M+H)
+] calculated value: 622.9996.Actual measurement: 622.9995.
Embodiment 113d
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2-hydroxyl-oxyethyl group)-5-(2-thienyl)-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
M.W.579.51?C
30H
24Cl
2N
2O
4S
With racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2-hydroxyl-oxyethyl group)-5-iodo-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone (150mg, 0.24mmol), triphenyl phosphine (Aldrich, 25mg), three (dibenzalacetones), two palladiums (Strem Chemicals, MA, 25mg), cupric iodide (2mg, Aldrich), and 2-(tributyl stannyl) thiophene (585mg, 1.56mmol Aldrich) merge in the 1.4-diox (4mL).Mixture is stirred 1.5h with nitrogen purging and at 85 ℃.Reaction mixture poured in the water and with EtOAc extract.With the organism H that merges
2O, MgSO is used in the salt water washing
4Dry and concentrated, obtain yellow residue.It separating with the enterprising circumstances in which people get things ready for a trip spectrum of the ISCO machine of EtOAc to 5%MeOH/EtOAc wash-out, is followed from CH
2Cl
2/ hexane recrystallization obtains pale solid.20mg。
HRMS (ES
+) m/z is to C
30H
24Cl
2N
2O
4S+H[(M+H)
+] measured value, 579.0905; Calculated value, 579.0907.
Embodiment 114
Preparation chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2-hydroxyl-oxyethyl group)-5-(2-furyl)-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
M.W.563.44?C
30H
24Cl
2N
2O
5
With racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2-hydroxyl-oxyethyl group)-5-iodo-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone (120mg, 0.19mmol), triphenyl phosphine (Aldrich, 30mg), three (dibenzalacetones), two palladiums (Strem Chemicals, MA, 20mg), CuI (2mg, and 2-(tributyl stannyl) furans (200mg, 0.56mmol Aldrich),, Aldrich) merge to 1, in the 4-diox (4mL).Mixture is stirred 1.5hrs with nitrogen purging and at 80 ℃.Reaction mixture poured in the water and with EtOAc extract.With the organism H that merges
2O, MgSO is used in the salt water washing
4Dry and concentrated, obtain yellow residue.It separating with the enterprising circumstances in which people get things ready for a trip spectrum of the ISCO machine of EtOAc to 5%MeOH/EtOAc wash-out, is obtained yellow film.32mg。Then with this product on the SFC machine with 2mL/min., 35% methyl alcohol, 100 crust and the fractionation of 30 ℃ condition obtain two enantiomorphs.
HRMS (ES
+) m/z is to C
30H
24Cl
2N
2O
5+ H[(M+H)
+] measured value, 563.1133; Calculated value, 563.1135.
Embodiment 115
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2-hydroxyl-oxyethyl group)-5-phenyl-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
M.W.573.48?C
32H
26Cl
2N
2O
4
With racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2-hydroxyl-oxyethyl group)-5-iodo-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone (200mg, 0.32mmol), triphenyl phosphine (Aldrich, 30mg), three (dibenzalacetones), two palladiums (Strem Chemicals, MA, 32mg), CuI (3mg, Aldrich), (587mg, 1.60mmol Aldrich) merge in the 1.4-diox (4mL) with the tributyl phenyltin.Mixture is stirred 2h with nitrogen purging and at 80 ℃.Reaction mixture is diluted with THF, pass through diatomite filtration.Filtrate is concentrated, obtain brown resistates, it separating with 50%EtOAc/ hexane to the enterprising circumstances in which people get things ready for a trip spectrum of the ISCO machine of EtOAc wash-out, then with the HPLC purifying that adopts 25-65%CH3CN/H2O, is obtained white solid.7.8mg。
HRMS (ES
+) m/z is to C
32H
26Cl
2N
2O
4+ H[(M+H)
+] measured value, 573.1340; Calculated value, 573.1343.
Embodiment 116a
The preparation intermediate 4-chloro-2-tertiary butyl-dimethylsilyl oxygen base-phenyl aldehyde
M.W.270.83?C
13H
19ClO
2Si
To the 5-chloro-2-hydroxyl-phenyl aldehyde that stirs (Aldrich, 7.83g, 50mmol) in the solution in methylene dichloride (150mL), add imidazoles (Aldrich, 3.72g, 54.6mmol) and the tertiary butyl-dimethyl-chloro-silane (Aldrich, 7.84g, 52mmol).With mixture at stirring at room 5hrs.The imidazoles (1.2g) that adds second section, and mixture stirred 1hr.Mixture is poured in the saturated sodium bicarbonate solution (150mL) then.Separate organic layer and use methylene dichloride (2x50mL) to extract water layer.Extract water, the salt water washing that merges and use dried over mgso.Remove and desolvate, obtain pale solid.13.62g。
Embodiment 116b
Preparation intermediate 1-[2-(tertiary butyl-dimethylsilyl oxygen base)-5-chloro-phenyl]-3-TMS oxygen base-2-azepine-1,3-butadiene
M.W.384.07?C
18H
30ClNO
2Si
2
To 1,1,1,3,3 of 0 ℃ stirring, (3.34g, 20mmol) in the solution, (2.5M 8mL) and with mixture stirs 15min. to the 3-hexamethyldisilazane slowly to add n-Butyl Lithium.Add THF (40mL) then, then add the 4-chloro-2-tertiary butyl-dimethylsilyl oxygen base-phenyl aldehyde (5.42g, 20mmol).With mixture at stirring at room 30min..Then, add chlorination trimethyl silicane (26mmol), Acetyl Chloride 98Min. (26mmol) and Trimethylamine (26mmol) and with mixture at stirring at room 1hr.Mixture is filled up and should fill up with the 30%EtOAc/ hexane wash and pass through fully to guarantee aza-diene by silica gel is short fast.Filtrate is concentrated and is directly used in next step in room temperature.
Embodiment 116c
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(tertiary butyl-dimethylsilyl oxygen base)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-)-2,6 '-dioxo-spiral shell [3H-indoles-3,3 '-piperidines]-1-t-butyl formate
M.W.700.17?C
35H
39Cl
3N
2O
5Si
With E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-t-butyl formate (3.89g, 10mmol) and 1-[5-chloro-2-(tertiary butyl-dimethylsilyl oxygen base)-phenyl]-3-TMS oxygen base-2-azepine-1,3-butadiene (20mmol) merges in the toluene (110mL).Mixture is stirred 2hrs at 110 ℃.Solvent is removed and resistates is carried out chromatographic separation (15%-35%EtOAc/ hexane), obtain foam.1.66g.MS(H
+)，701。
Embodiment 116d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(2-pyrazinyl oxygen base)-phenyl]-spiral shell-[3H-indoles-3,3 '-piperidines]-2,6 '-diketone
M.W.565.85，C
28H
19Cl
3N
4O
3
To the racemize (2 ' R that stirs, 3R, 4 ' S)-2 '-[2-(tertiary butyl-dimethylsilyl oxygen base)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-)-2, (140mg is 0.2mmol) 1 for 6 '-dioxo-spiral shell [3H-indoles-3,3 '-piperidines]-1-t-butyl formate, solution in the 4-diox (4mL), add four-butyl Neutral ammonium fluoride (Aldrich, 0.4mmol, the solution of the 1M of 0.4mL in THF) and with mixture at stirring at room 30min..(Aldrich 0.40mmol) and with the mixture that obtains stirs 8hrs under refluxing to add 2-chloro-pyrazine then.Solvent removed and resistates is separated (dichloromethane solution of 5%MeOH) in the enterprising circumstances in which people get things ready for a trip spectrum of ISCO machine, obtain brown solid.24mg。MS(H
+)，565
Embodiment 117a
The preparation intermediate 4-iodo-2-tertiary butyl-dimethylsilyl oxygen base-phenyl aldehyde
M.W.362.29?C
13H
19IO
2Si
To the 5-iodo-2 hydroxyls-phenyl aldehyde that stirs (Aldrich, 15.5g, 62.5mmol) in the solution in methylene dichloride (100mL), add imidazoles (Aldrich, 4.28g, 63mmol) and the tertiary butyl-dimethyl-chloro-silane (Aldrich, 9.45g, 63mmol).Mixture is poured in the 1N sodium hydroxide solution (150mL) then at stirring at room 5.5hrs.Separate organic layer and with methylene dichloride (2x50mL) aqueous layer extracted.Extract water, the salt water washing that merges and use dried over mgso.Remove and desolvate, obtain oily matter,, obtain colorless oil its chromatographic separation (hexane is as eluent).16.6g。
Embodiment 117b
Preparation intermediate 1-[5-bromo-2-(tertiary butyl-dimethylsilyl oxygen base)-phenyl]-3-TMS oxygen base-2-azepine-1,3-butadiene
M.W.475.52?C
18H
30INO
2Si
2
To 1,1,1,3,3 of 0 ℃ stirring, the 3-hexamethyldisilazane (6.4g, 40mmol) in the solution, slowly just adding-(2.5M 16mL) and with mixture stirs 15min. to butyllithium.Add THF (80mL) then, then add the 4-iodo-2-tertiary butyl-dimethylsilyl oxygen base-phenyl aldehyde (14.48g, 40mmol).With mixture at stirring at room 30min..Then, add chlorination trimethyl silicane (40mmol), Acetyl Chloride 98Min. (40mmol) and Trimethylamine (40mmol) and with mixture at stirring at room 1hr.Mixture is filled up and should fill up and use the 30EtOAc/ hexane wash by silica gel is short fast, pass through fully to guarantee aza-diene.Filtrate is concentrated and is directly used in next step in room temperature.
Embodiment 117c
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(tertiary butyl-dimethylsilyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-)-2,6 '-dioxo-spiral shell [3H-indoles-3,3 '-piperidines]-1-t-butyl formate
M.W.793.61?C
35H
39Cl
2IN
2O
5Si
With E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-t-butyl formate (3.85g, 13mmol) and 1-[5-bromo-2-(tertiary butyl-dimethylsilyl oxygen base)-phenyl]-3-TMS oxygen base-2-azepine-1,3-butadiene (40mmol) merges in the toluene (110mL).Mixture is stirred 2hrs at 110 ℃.Solvent is removed and, obtained foam resistates chromatographic separation (15%-35%EtOAc/ hexane).4.65g.MS(H
+)，693。
Embodiment 117d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
M.W.579.23?C
24H
17Cl
2IN
2O
3
With racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(tertiary butyl-dimethylsilyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-)-2,6 '-dioxo-spiral shell [3H-indoles-3,3 '-piperidines]-(200mg 0.25mmol) is dissolved in 30%TFA/CH to the 1-t-butyl formate
2Cl
2(5mL), and with solution at stirring at room 2h.Solvent is removed and resistates is distributed between water and methylene dichloride.Separate organic layer and with dried over sodium sulfate and concentrated.With the resistates chromatographic separation, obtain white solid, it is directly used in next step.MS(H
+)，579。
Embodiment 117e
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-(2-furyl)-2-hydroxyl-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
M.W.519.39，C
28H
20Cl
2N
2O
4
With with in the similar mode of method described in the embodiment 114, by racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone prepares title compound.
HRMS (ES
+) m/z is to C
28H
20Cl
2N
2O
4+ H[(M+H)
+] measured value, 519.0873; Calculated value, 519.0873
Embodiment 118
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-(2-thio-furan base)-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
M.W.535.45，C
28H
20Cl
2N
2O
3S
With with in the similar mode of method described in the embodiment 113d, by racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone prepares title compound.
MS (ES
+) m/z is to C
28H
20Cl
2N
2O
3S+H[(M+H)
+] measured value, 535; Calculated value, 534.
Embodiment 119
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-phenyl]-phenyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
M.W.529.43，C
30H
22Cl
2N
2O
3
With with in the similar mode of method described in the embodiment 115, by racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone prepares title compound.
HRMS (ES
+) m/z is to C
30H
22Cl
2N
2O
3+ H[(M+H)
+] measured value, 529.1080; Calculated value, 529.1080.
Embodiment 120
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-(2-thiazolyl)-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
M.W.536.44，C
27H
19Cl
2N
3O
3S
With with in the similar mode of method described in the embodiment 113d, by racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone (214d) and 4-(tributyl stannyl) thiazole (Synthonix) preparation title compound.
HRMS (ES
+) m/z is to C
27H
19Cl
2N
3O
3S+H[(M+H)
+] measured value, 536.0598; Calculated value, 536.0597.
Embodiment 121
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-(2-thiazolyl)-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
M.W.536.44，C
27H
19Cl
2N
3O
3S
With with in the similar mode of method described in the embodiment 113d, by racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone and 2-(tributyl stannyl) thiazole (Synthonix) preparation title compound.
HRMS (ES
+) m/z is to C
27H
19Cl
2N
3O
3S+H[(M+H)
+] measured value, 536.0598; Calculated value, 536.0597.
Embodiment 122a
Preparation intermediate (S)-3-(4-chloro-2-formyl radical-phenoxy group)-tetramethyleneimine-1-t-butyl formate
M.W.325.79，C
16H
20ClNO
4
(4.89g, 26.12mmol is Aldrich) at CH to (R)-1-N-boc-3-hydroxyl pyrrolidine of 0 ℃
2Cl
2In the solution (100mL), add methylsulfonyl chloride, then add Et
3N (4.4mL, 31.35mmol).Reactant at stirring at room 2h, is used 0.5N HCl, and MgSO is used in water and salt water washing
4Drying is filtered and is concentrated, and obtains faint yellow oily thing.
With this yellow oil and 5-chloro-salicylic aldehyde (4.07g, 26mmol, Aldrich) and Cs
2CO
3(21.2g 65mmol) merges in DMF (100ml), 75 ℃ of heated overnight, pours in the water and with EtOAc (3x) and extracts.With the organism 0.5N NaOH that merges, water, salt water washing, MgSO
4Drying is filtered and is concentrated, and obtains deep yellow oily thing (6.82g, 80% yield), and it is directly used in next step.
Embodiment 122b
Preparation chirality (2 ' R, 3R, 4 ' S)-2 '-2-[3-(tertbutyloxycarbonyl)-pyrroles's alkoxyl group]-5-chloro-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW?656.9991?C
33H
32Cl
3N
3O
5
With with at embodiment 48C, the similar mode of method described in the 48d is by intermediate (R)-3-(4-chloro-2-formyl radical-phenoxy group)-tetramethyleneimine-1-t-butyl formate (MS (H
+), 656) beginning, with 2 steps preparation title diastereomer compound (RO5254307-000).SFC is further purified with chirality, obtain chirality (2 ' R, 3R, 4 ' S)-2 '-{ 2-[3-(tertbutyloxycarbonyl)-pyrroles's alkoxyl group]-5-chloro-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone (RO5254767-000)
HRMS (ES
+) m/z is to C
33H
32Cl
3N
3O
5+ H[(M+H)
+] measured value, 656.1481; Calculated value, 656.1481.
Embodiment 123
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-(3-pyrroles's alkoxyl group)-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW?556.8808?C
28H
24Cl
3N
3O
3
With racemize (2 ' R, 3R, 4 ' S)-2 '-{ 2-[3-(tertbutyloxycarbonyl)-pyrroles's alkoxyl group]-5-chloro-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2, (800mg 1.22mmol) is dissolved in 30%TFA/CH to 6 '-diketone
2Cl
2(15mL) and with solution at stirring at room 30min.Remove desolvate and with resistates at EtOAc and 10%Na
2CO
3Between distribute.Separate organic layer, water, salt water washing and with dried over sodium sulfate and concentrated.Obtain yellow solid, it is directly used in next step.MS(H
+)，556。
In a similar fashion, by chirality (2 ' R, 3R, 4 ' S)-2 '-{ 2-[3-(tertbutyloxycarbonyl)-pyrroles's alkoxyl group]-5-chloro-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone prepares title compound.MS(H
+)，556。
Embodiment 124
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(3-methylsulfonyl-pyrroles's alkoxyl group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW?634.97?C
29H
26Cl
3N
3O
5S
With with in the similar mode of method described in the embodiment 13a, by chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-(3-pyrroles's alkoxyl group)-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone (RO5256628-000) preparation title compound.
HRMS (ES
+) m/z is to C
29H
26Cl
3N
3O
5S+H[(M+H)
+] measured value, 634.0729; Calculated value, 634.0732.
Embodiment 125
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(3-ethylamino formyl radical-pyrroles's alkoxyl group)-phenyl }-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
627.96?C
31H
29Cl
3N
4O
4
With with in the similar mode of method described in the embodiment 29, by racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-(3-pyrroles's alkoxyl group)-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone prepares title compound.Chirality SFC separates subsequently, obtains title compound.
HRMS (ES
+) m/z is to C
31H
29Cl
3N
4O
4+ H[(M+H)
+] measured value, 627.1324; Calculated value, 627.1327.
Embodiment 126
Preparation chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-3-pyrroles's alkoxyl group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
M.W.570.91，C
29H
26Cl
3N
3O
3
With with in the similar mode of method described in the embodiment 6a, by chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-(3-pyrroles's alkoxyl group)-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone prepares title compound.
HRMS (ES
+) m/z C
29H
26Cl
3N
3O
3+ H[(M+H)
+]: measured value, 570, calculated value, 570.
Embodiment 127a
Preparation intermediate 7-oxa--3-aza-bicyclo [4.1.0] heptane-3-t-butyl formate
M.W.199.25，C
10H
17NO
3
To 3 of 0 ℃ stirring, and 6-dihydro-2H-pyridine-1-t-butyl formate (Aldrich, 15.99g, 87.28mmol) in the solution in methylene dichloride (600mL), adding mCPBA (Aldrich, 29.4g, 77%, 131mmol) and with the mixture stirring spend the night.To react and use 10%Na
2S
2O
3Quencher, and separate organic layer, use 5% yellow soda ash, salt solution and water washing, and, obtain faint yellow oily thing with dried over sodium sulfate and concentrated, with its chromatographic separation (10%EtOAc/ hexane), obtain colorless oil.14.93g。This compound is directly used in next step.
Embodiment 127b
Preparation intermediate racemize 4-(2-formyl radical-4-iodo-phenoxy group)-3-hydroxy-piperdine-1-t-butyl formate
M.W.447，C
17H
22INO
5
To the 2-hydroxyl-5-iodo-phenyl aldehyde (Aldrich that stirs, 4.96g, 20mmol) in the solution in DMF (80mL), add salt of wormwood (10g, 60mmol) with 7-oxa--3-aza-bicyclo [4.1.0] heptane-3-t-butyl formate (8g, 40mmol), and with mixture stirred 3 days and stirred 2 days at 80 ℃ at 70 ℃.
Mixture poured among the 1N HCl and with EtOAc (3x50mL) extraction mixture.With the extract merging and with dried over sodium sulfate and concentrated, obtain oily matter, it is separated (10-30%EtOAc/ hexane) in the enterprising circumstances in which people get things ready for a trip spectrum of ISCO machine, obtain oily matter, 3.4g.MS(H
+)，348。
Embodiment 127c
Preparation intermediate 3-(tertiary butyl-dimethyl-silanyloxy base)-4-(2-formyl radical-4-iodo-phenoxy group)-piperidinyl-1-t-butyl formate
M.W.561.54，C
23H
36INO
5Si
In 0 ℃; to 4-(2-formyl radical-4-iodo-the phenoxy group)-3-hydroxy-piperdine-1-t-butyl formate (1.12g that stirs; 2.50mmol) in the solution in DMF (7mL); add 2,6-lutidine (Aldrich, 1.16mL; 10mmol); (Aldrich 10mmol), and stirs 40min. with mixture then to add TBDSOTf.Reaction mixture poured in the water and with EtOAc (3x25mL) extract.Extract is merged and drying and concentrated, obtain yellow oil.1.6g。It is passed through chromatography purification.MS(H
+)，562。
Embodiment 127d
Preparation intermediate 3-(tertiary butyl-dimethyl-silanyloxy base)-4-[4-iodo-2-(2-azepine-3-TMS oxygen Ji-Ding-butadienyl)-phenoxy group]-piperidines-1-t-butyl formate
M.W.674.77，C
28H
47IN
2O
5Si
2
(Aldrich, 0.50mL are slowly just adding-butyllithium that (in hexane, 0.96mL 2.4mmol), and stirs 5min. with mixture for Aldrich, 2.5M in 2.4mmol) to two (TMS) amine aqueous solutions of-20 ℃ stirrings.Add THF (10mL), then be added in 3-(tertiary butyl-dimethyl-silanyloxy base)-4-(2-formyl radical-4-iodo-phenoxy group)-piperidinyl-1-t-butyl formate (2.4mmol, as above preparation) among the 10mLTHF.Mixture progressively is warming to rt and stirs 1hr.With reactant be cooled to 0 ℃ and add TMSCl (Aldrich, 2.4mmol), Et3N (Aldrich, 2.4mmol) and Acetyl Chloride 98Min. (Aldrich 2.4mmol), and stirs 2hrs with mixture.Then mixture is filtered by the short pad of diatomite, and filtrate is under reduced pressure concentrated, obtain the deep yellow paste, it is directly used in next step.
Embodiment 127e
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[trans-4-(3-hydroxyl-1-methylsulfonyl-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
M.W.757，C
30H
28Cl
2IN
3O
6S
With 3-(tertiary butyl-dimethyl-silanyloxy base)-4-[4-iodo-2-(2-azepine-3-TMS oxygen Ji-Ding-1, the 3-dialkylene)-phenoxy group]-E/Z-6-chloro-3-[1-(3-chloro-phenyl)-methylene radical among piperidines-1-t-butyl formate (2.4mmol) and the embodiment 1b]-2-oxo-2, (375mg 0.96mmol) merges in the toluene of 10mL and with mixture and stirs 14h at 125 ℃ 3-dihydro-indoles-1-t-butyl formate.Under reduced pressure except that desolvating and, obtaining yellow foam with resistates chromatographic separation (EtOAc/ hexane, 0% to 40%) on the ISCO machine.324mg。
(250mg 0.28mmol) is dissolved among the THF of 5mL with solid.In the solution that stirs, add tetrabutyl ammonium fluoride (Aldrich, the THF solution of 1M, 0.6mL) and with mixture in stirred overnight at room temperature.Except that desolvating and resistates being dissolved in the methylene dichloride and trifluoroacetic acid (1: 1) of 4mL.Mixture at stirring at room 30min. and except that desolvating, is obtained foam, it is directly used in next step.
Solid is dissolved among the THF (3mL).In the solution that stirs, add saturated sodium bicarbonate (1.5mL), then add methylsulfonyl chloride (Aldrich, 2eq, 0.56mmol).Reaction mixture is extracted at stirring at room 1h with EtOAc (3x5mL).Extract is merged and drying.Resistates is gone up purifying at reversed-phase HPLC (30-70 acetonitrile/water), obtain white powder.9mg。MS(H
+)，756。
Embodiment 128a
Preparation intermediate 5-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl aldehyde
MW?224.23，C
12H
13FO
3
With with in the similar mode of method described in the embodiment 4a, 5-fluorine salicylic aldehyde (Aldrich) and methylsulfonic acid tetrahydrochysene-pyrans-4-base ester (embodiment 32a) and salt of wormwood are reacted in dimethyl formamide, obtain solid.MS(H
+)，225。
Embodiment 128b
Preparation intermediate 1-[5-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
MW?337.47，C
17H
24FNO
3Si
With with in the similar mode of method described in the embodiment 112b, with 5-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl aldehyde LHMDS, Acetyl Chloride 98Min., triethylamine and chloro-triethyl-silane treatment obtain required compound, and it is directly used in next step.
Embodiment 128c
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-[5-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW?555，C
29H
25Cl
2FN
2O
4
With with the similar mode of the preparation of embodiment 1e, the 6-chloro-3-[1-that will in embodiment 1b, prepare (3-chloro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[5-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1, the reaction of 3-divinyl obtains required product.MS(M+H
+)，555。
Embodiment 129a
Preparation intermediate 6-chloro-3-[1-(3-fluoro-phenyl)-methylene radical]-1, the 3-dihydro-indol-2-one
M.W?237.7，C
15H
9ClFNO
Usefulness 3-fluoro-phenyl aldehyde in methyl alcohol (50mL) and piperidines (0.2mL) (Aldrich, 5.57g 44.92mmol) handle 6-chloro-1, and the 3-dihydro-indol-2-one (Aldrich, 7.5g, 44.92mmol).With mixture at 75 ℃ of heated overnight cool to room temperature then.With solid filtering and drying, obtain yellow solid.8.8g。
Embodiment 129b
Preparation intermediate 6-chloro-3-[1-(3-fluoro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate
M.W?373.8，C
20H
17ClFNO
3
At the DMAP of methylene dichloride (50mL) and catalytic amount (Aldrich, 25mg) middle use (t-BuOCO)
2O (Aldrich, 3.05g 14mmol) handle 6-chloro-3-[1-(3-fluoro-phenyl)-methylene radical]-1, the 3-dihydro-indol-2-one (3.8g, 13.1mmol).Mixture is washed and uses dried over sodium sulfate fast at stirring at room 5h with 0.05N HCl.Remove and desolvate, obtain yellow solid.4.1g。
Embodiment 129c
Preparation chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-fluoro-phenyl)-2 '-[5-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW?538.98，C
29H
25ClF
2N
2O
4
With with the similar mode of the preparation of embodiment 1e, make 6-chloro-3-[1-(3-fluoro-the phenyl)-methylene radical that in embodiment 129b, prepares]-2-oxo-2, the 1-[5-fluoro-2-for preparing among 3-dihydro-indoles-1-t-butyl formate and the embodiment 128b (tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.MS(M+H
+)，539。
Chirality SFC separates (30%MeOH, 100Par, 30 ℃) and obtains required enantiomorph.MS(M+H
+)，539。
Embodiment 130a
Preparation intermediate methylsulfonic acid tetrahydrochysene-thiapyran-4-base ester
MW?196.29，
C6H12O3S2
(Aldrich, 2.0g in dichloromethane solution 17mmol), slowly add methylsulfonyl chloride (18mmol) and triethylamine (18mmol) and mixture are stirred 1h to the 4-of 0 ℃ stirring hydroxyl-tetrahydrochysene-thiapyran.Water quencher reaction and use the dichloromethane extraction mixture.Extract merged and use dried over sodium sulfate.Removing desolvates obtains pale solid.2.15g。
Embodiment 130b
Preparation intermediate 5-fluoro-2-(tetrahydrochysene-thiapyran-4-base oxygen base) phenyl aldehyde
MW?240，C
12H
13FO
2S
With with in the similar mode of method described in the embodiment 128a, 5-fluorine salicylic aldehyde (Aldrich) and methylsulfonic acid tetrahydrochysene-thiapyran of preparing in embodiment 130a-4-base ester and salt of wormwood are reacted in dimethyl formamide, obtain solid.MS(H
+)，241。
Embodiment 130c
Preparation intermediate 1-[5-fluoro-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
With with in the similar mode of method described in the embodiment 112b, with 5-fluoro-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl aldehyde LHMDS, Acetyl Chloride 98Min., triethylamine and trimethyl silane processing obtain required compound, and it is directly used in next step.
Embodiment 130d
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，571.5，C
29H
25Cl
2FN
2O
3S
With with the similar mode of the preparation of embodiment 1e, the 6-chloro-3-[1-that will in embodiment 1b, prepare (3-chloro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and the 1-[5-fluoro-2-that in embodiment 130c, prepares (tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.MS(M+H
+)，571。
Embodiment 131
Preparation chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(1,1-dioxo-tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW?603.5，C
29H
25Cl
2FN
2O
5S
To the racemize (2 ' R that stirs, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2, in the solution of 6 '-diketone (300mg) in methylene dichloride (15mL), add MCPBA (Aldrich, 77%, 180mg 0.79mmol) and with the mixture stirring spends the night.With saturated sodium thiosulfate solution quencher reaction, separate organic layer and with sodium hydrogen carbonate solution washing and drying (MgSO
4).Remove and to desolvate, obtain thick product, with it at ISCO machine (EtOAc/CH
2Cl
2) go up chromatogram and be separated into required product, be white solid.72mg。MS(M+H
+)，603。
With racemoid on SFC at 30%MeOH, further separate under 100Par and 30 ℃ the condition, obtain enantiomorph.26mg。
MS(M+H
+)，603。
Embodiment 132a
Preparation intermediate methylsulfonic acid cyclohexyl
MW?178，C
7H
14O
3S
To the hexalin of 0 ℃ stirring (Aldrich, 10.2g, 100mmol) in the solution in methylene dichloride (250mL), slowly add methylsulfonyl chloride (8.52mL, 110mmol) and triethylamine (17.5mL 125mmol) and with mixture stirs 2hrs.The water quencher is reacted and mixture is washed with 0.5N HCl and salt brine solution.Use the dried over sodium sulfate organic layer.Remove and desolvate, obtain yellow oil.18.05g。
Embodiment 132b
Preparation intermediate 5-fluoro-2-cyclohexyl-phenyl aldehyde
MW，222.26，C
13H
15FO
2
With with in the similar mode of method described in the embodiment 4a, 5-fluorine salicylic aldehyde (Aldrich) and methylsulfonic acid cyclohexyl and salt of wormwood are reacted in dimethyl formamide, obtain solid.MS(H
+)，223。
Embodiment 132c
Preparation intermediate 1-[5-fluoro-2-(cyclohexyl oxygen base)-phenyl]-3-TMS oxygen base-2-azepine-1,3-butadiene
MW?335.5，C
18H
26FNO
2Si
With with in the similar mode of method described in the embodiment 112b, with 5-fluoro-2-(cyclohexyl oxygen base)-phenyl aldehyde LHMDS, Acetyl Chloride 98Min., triethylamine and chloro-trimethylammonium-silane treatment obtain required compound, and it is directly used in next step.
Embodiment 132d
Preparation chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(cyclohexyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW?552.14，C
30H
27Cl
2FN
2O
3
With with the similar mode of the preparation of embodiment 1e, make 6-chloro-3-[1-(3-chloro-the phenyl)-methylene radical for preparing among the embodiment 1b]-2-oxo-2, the 1-[5-fluoro-2-for preparing among 3-dihydro-indoles-1-t-butyl formate and the embodiment 132c (cyclohexyl oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1, the reaction of 3-divinyl obtains required product.MS(M+H
+)，553。
With racemoid on SFC at 30%MeOH, further separate under 100Par and 30 ℃ the condition, obtain enantiomorph.
MS(M+H
+)，553。
Embodiment 133a
Preparation intermediate methylsulfonic acid ring pentyl ester
M.W，164，C
6H
12O
3S
To the cyclopentanol of 0 ℃ stirring (Aldrich, 2.58g, 30mmol) in the solution in methylene dichloride (150mL), slowly add methylsulfonyl chloride (2.55mL, 33mmol) and triethylamine (5.23mL 37.5mmol) and with mixture stirs 1.5hrs.The water quencher is reacted and mixture is washed with 0.5N HCl and salt brine solution.Use the dried over sodium sulfate organic layer.Remove and desolvate, obtain colorless oil.5.1g。
Embodiment 133b
Preparation intermediate 2-cyclopentyloxy-5-fluoro-phenyl aldehyde
MW，220.26，C
12H
13FO
2
With with in the similar mode of method described in the embodiment 4a, 5-fluorine salicylic aldehyde (Aldrich) and the methylsulfonic acid ring pentyl ester and the salt of wormwood that prepare in embodiment 133a are reacted in dimethyl formamide, obtain light yellow oil.MS(H
+)，221。
Embodiment 133c
Preparation intermediate 1-[5-fluoro-2-(cyclopentyloxy)-phenyl]-3-TMS oxygen base-2-azepine-1,3-butadiene
MW，321.5，C
17H
24FNO
2Si
With with in the similar mode of method described in the embodiment 112b, with 5-fluoro-2-(cyclopentyloxy)-phenyl aldehyde LHMDS, Acetyl Chloride 98Min., triethylamine and chloro-trimethylammonium-silane treatment obtain required compound, and it is directly used in next step.
Embodiment 133d
Preparation chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(cyclopentyloxy)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，539.44，C
29H
25Cl
2FN
2O
3
With with the similar mode of the preparation of embodiment 1e, make 6-chloro-3-[1-(3-chloro-the phenyl)-methylene radical that in embodiment 1b, prepares]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[5-fluoro-2-(the cyclopentyloxy)-phenyl that in embodiment 133c, prepares]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.MS(M+H
+)，539。
By chirality SFC (30%MeOH, 100Par, 30 ℃) separation of racemic thing, obtain required enantiomorph.
Embodiment 134a
Preparation intermediate 5-chloro-2-cyclohexyl oxygen base-phenyl aldehyde
MW，238.72，C
13H
15ClO
2
With with in the similar mode of method described in the embodiment 4a, 5-chloro-salicylic aldehyde (Aldrich) and the methylsulfonic acid cyclohexyl and the salt of wormwood that prepare in embodiment 132a are reacted in dimethyl formamide, obtain solid.MS(H
+)，239。
Embodiment 134b
Preparation intermediate 1-[5-chloro-2-(cyclohexyl oxygen base)-phenyl]-3-TMS oxygen base-2-azepine-1,3-butadiene
MW?351.14，C
18H
26ClNO
2Si
With with in the similar mode of method described in the embodiment 112b, with 5-chloro-2-cyclohexyl oxygen base-phenyl aldehyde LHMDS, Acetyl Chloride 98Min., triethylamine and chloro-trimethylammonium-silane treatment obtain required compound, and it is directly used in next step.
Embodiment 134c
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(cyclohexyl oxygen base-phenyl)]-4 '-(3-chloro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，569.91，C
30H
27Cl
3N
2O
3
With with in the similar mode of method described in the embodiment 1e, with 6-chloro-3-[1-(3-chloro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[5-chloro-2-(cyclohexyl oxygen base)-phenyl]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains white solid.
MS(M+H
+)，569.
Embodiment 135a
Preparation intermediate 5-chloro-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl aldehyde
MW，256.75，C
12H
13ClO
2S
With with in the similar mode of method described in the embodiment 4a, 5-chloro-salicylic aldehyde (Aldrich) is reacted in dimethyl formamide with methylsulfonic acid tetrahydrochysene-thiapyran of preparing in embodiment 130a-4-base ester and salt of wormwood, obtain solid.MS(H
+)，257。
Embodiment 135b
Preparation intermediate 1-[5-chloro-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
With with in the similar mode of method described in the embodiment 112b, with 5-chloro-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl aldehyde LHMDS, Acetyl Chloride 98Min., triethylamine and trimethyl silane processing obtain required compound, and it is directly used in next step.
Embodiment 135c
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chlorine 2 '-[5-chloro-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl]-4 '-(3-fluoro-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，571.50，C
29H
25Cl
2FN
2O
3S
With with the similar mode of the preparation of embodiment 1e, the 6-chloro-3-[1-that will in embodiment 129b, prepare (3-fluoro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[5-chloro-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.
MS(M+H
+)，571。
Embodiment 136
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(1,1-dioxo-tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，603.50，C
29H
25Cl
2FN
2O
3S
With with the similar mode of the preparation of embodiment 131, with (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-fluoro-phenyl)-2 '-[5-chloro-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone and MCPBA reaction obtain required product.MS(M+H
+)，603。
Embodiment 137a
Preparation intermediate 1-[5-fluoro-2-(4-fluoro-phenoxy group)-phenyl]-3-TMS oxygen base-2-azepine-1,3-butadiene
MW，347.44，C
18H
19F2NO
2Si
With with in the similar mode of method described in the embodiment 112b, 5-fluoro-2-(4-fluoro-phenyl oxygen base)-phenyl aldehyde (VWR) is used LHMDS, Acetyl Chloride 98Min., triethylamine and chloro-trimethylammonium-silane treatment obtain required compound, and it is directly used in next step.
Embodiment 137b
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-fluoro-phenyl)-2 '-[5-fluoro-2-(4-fluoro-phenoxy group-phenyl)] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，548.95，C
30H
20ClF
3N
2O
3
With with in the similar mode of method described in the embodiment 1e, the 6-chloro-3-[1-that will in embodiment 129b, prepare (3-fluoro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[5-fluoro-2-(4-fluoro-phenoxy group)-phenyl]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains white solid.
MS(M+H
+)，549。
Embodiment 138a
Preparation intermediate 1-[5-fluoro-2-(2,4-two fluoro-phenyl oxygen bases)-phenyl]-3-TMS oxygen base-2-azepine-1,3-butadiene
MW，365.43，C
18H
18F
3NO
2Si
With with in the similar mode of method described in the embodiment 112b, 5-fluoro-2-(2,4-fluoro-phenyl oxygen base)-phenyl aldehyde (VWR) is used LHMDS, Acetyl Chloride 98Min., triethylamine and chloro-trimethylammonium-silane treatment obtain required compound, and it is directly used in next step.
Embodiment 138b
Preparation intermediate 3-[1-(3-chloro-phenyl)-methylene radical]-6-fluoro-2-oxo-2,3-dihydro-indoles-1-t-butyl formate
M.W?373.81，C
20H
17ClFNO
3
With with the similar mode of the method for in embodiment 1a and 1b, describing, with 6-fluoro-1, the reaction of 3-dihydro-indol-2-one (Aldrich) and 3-chloro-phenyl aldehyde, obtain 6-fluoro-3-[1-(2,5-two fluoro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles, with its subsequently with (t-BuOCO)
2O and DMAP reaction, and be directly used in next step.
Embodiment 138c
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-4 '-(3-chloro-phenyl)-6-fluoro-2 '-[2-(2,4-two fluoro-phenyl oxygen bases)-5-fluoro-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，566.94，C
30H
19ClF
4N
2O
3
With with the similar mode of the preparation of embodiment 1e, with 6-fluoro-3-[1-(3-chloro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[2-(2,4-two fluoro-phenyl oxygen bases)-5-fluoro-phenyl]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.
MS(M+H
+)，567。
Embodiment 139a
Preparation intermediate 5-chloro-2-[(2-chloro-6-fluoro-benzyloxy)-phenyl]-3-TMS oxygen base-2-azepine-1,3-butadiene
MW，411，C
19H
20Cl
2FNO
2Si
With with in the similar mode of method described in the embodiment 112b, 5-chloro-2-(2-chloro-6-fluoro-benzyloxy)-phenyl aldehyde (Chembrdg-BB) is used LHMDS, Acetyl Chloride 98Min., triethylamine and chloro-trimethylammonium-silane treatment, obtain required compound, it is directly used in next step.
Embodiment 139b
Preparation intermediate 6-chloro-3-[1-(2,5-two fluoro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate
M.W?391.81，C
20H
16ClF
2NO
3
With with the similar mode of the method for in embodiment 1a and 1b, describing, with 6-chloro-1,3-dihydro-indol-2-one (Aldrich) and 2, the reaction of 5-two fluoro-phenyl aldehydes obtains 6-chloro-3-[1-(2,5-two fluoro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles, with its subsequently with (t-BuOCO)
2O and DMAP reaction.
Embodiment 139c
Preparation racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[5-chloro-2-(2-chloro-6-fluoro-benzyloxy)-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，631.86，C
31H
20Cl
3F
3N
2O
3
With with the similar mode of the method for in embodiment 1e, describing, with 6-chloro-3-[1-(2,5-two fluoro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 5-chloro-2-[(2-chloro-6-fluoro-benzyloxy)-phenyl]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.
MS(M+H
+)，631。
Embodiment 140a
Preparation intermediate 2-(4-cyano-phenyl oxygen base)-5-fluoro-phenyl aldehyde
MW，241，C
14H
18FNO
2
(Aldrich, 5.00g 42mmol) in the solution in DMF (100mL), add salt of wormwood (63mmol) and 2-4, and (Aldrich, 5.97g's two fluoro-phenyl aldehydes 42mmol) and with mixture spend the night 90 ℃ of stirrings to the 4-cyanophenol that stirs.With the mixture cool to room temperature and pour in the water.With solid filtering and drying, obtain light yellow solid.5.2g?MS(H
+)，242。
Embodiment 140b
Preparation intermediate 1-[2-(4-cyano group-phenyl oxygen base)-5-fluoro-phenyl]-3-trimethylsiloxy-2-azepine-1,3-butadiene
MW，359，C
19H
19FN
2O
2Si
With with in the similar mode of method described in the embodiment 112b, with 2-(4-cyano group-phenyl oxygen base)-5-fluoro-phenyl aldehyde LHMDS, Acetyl Chloride 98Min., triethylamine and chloro-trimethylammonium-silane treatment obtain required compound, and it is directly used in next step.
Embodiment 140c
Preparation racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[2-(4-cyano group-phenyl oxygen base)-5-fluoro-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，573.96，C
31H
19ClF
3N
3O
3
With with the similar mode of the method for in embodiment 1e, describing, the 6-chloro-3-[1-(2 that will in embodiment 139b, prepare, 5-two fluoro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[2-(4-cyano group-phenyl oxygen base)-5-fluoro-phenyl]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.MS(M+H
+)，573。
Embodiment 141
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[2-(4-cyano group-phenyl oxygen base)-5-fluoro-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，555.96，C
31H
20ClF
2N
3O
3
With with the similar mode of the method for in embodiment 1e, describing, the 6-chloro-3-[1-that will in embodiment 129b, prepare (3-fluoro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[2-(4-cyano group-phenyl oxygen the base)-5-fluoro-phenyl that in embodiment 140b, prepares]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.
MS(M+H
+)，556。
Embodiment 142
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-4 '-(3-chloro-phenyl)-2 '-[2-(4-cyano group-phenyl oxygen base)-5-fluoro-phenyl]-6-fluorine spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，555.96，C
31H
20ClF
2N
3O
3
With with the similar mode of the method for in embodiment 1e, describing, the 6-fluoro-3-[1-that will in embodiment 138b, prepare (3-chloro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[2-(4-cyano group-phenyl oxygen the base)-5-fluoro-phenyl that in embodiment 140b, prepares]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.
MS(M+H
+)，556。
Embodiment 143a
Preparation intermediate 2-(4-methoxyl group-phenyl oxygen base)-5-fluoro-phenyl aldehyde
MW，246，C
14H
11FO
3
With with the similar mode of the method for in embodiment 140a, describing, with 2,4-two fluoro-phenyl aldehydes (Aldrich) and 4-methoxyl group-phenol and salt of wormwood reaction obtain solid.MS(H
+)，247。
Embodiment 143b
Preparation intermediate 1-[5-fluoro-2-(4-methoxyl group-phenyl oxygen base)-phenyl]-3-TMS oxygen base-2-azepine-1,3-butadiene
MW，359，C
19H
22FNO
3Si
With with in the similar mode of method described in the embodiment 112b, with 2-(4-methoxyl group-phenyl oxygen base)-5-fluoro-phenyl aldehyde LHMDS, Acetyl Chloride 98Min., triethylamine and chloro-trimethylammonium-silane treatment obtain required compound, and it is directly used in next step.
Embodiment 143c
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-fluoro-2-(4-methoxyl group-phenyl oxygen base)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，560.98，C
31H
23ClF
2N
2O
4
With with the similar mode of the method for in embodiment 1e, describing, make 6-chloro-3-[1-(3-two fluoro-the phenyl)-methylene radical that in embodiment 129b, prepares]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[2-(4-methoxyl group-phenyl oxygen base)-5-fluoro-phenyl]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.
MS(M+H
+)，561。
Embodiment 144
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-4 '-(3-chloro-phenyl)-6-fluoro-2 '-[5-fluoro-2-(4-methoxyl group-phenyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，560.98，C
31H
23ClF
2N
2O
4
With with the similar mode of the method for in embodiment 1e, describing, the 6-fluoro-3-[1-that will in embodiment 138b, prepare (3-chloro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[2-(4-methoxyl group-phenyl oxygen the base)-5-fluoro-phenyl that in embodiment 143b, prepares]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.MS(M+H
+)，561。
Embodiment 145
Preparation racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[5-fluoro-2-(4-methoxyl group-phenyl oxygen base)-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，578.97，C
31H
22ClF
3N
2O
4
With with the similar mode of the method for in embodiment 1e, describing, make the 6-chloro-3-[1-(2 that in embodiment 139b, prepares, 5-two fluoro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 5-fluoro-1-[2-(4-methoxyl group-phenyl oxygen the base)-phenyl that in embodiment 143b, prepares]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.
MS(M+H
+)，579。
Embodiment 146
Preparation chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-[5-fluoro-2-(4-methoxyl group-phenyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，577.43，C
31H
23Cl
2FN
2O
4
With with the similar mode of the method for in embodiment 1e, describing, make 6-chloro-3-[1-(3-chloro-the phenyl)-methylene radical that in embodiment 1b, prepares]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[2-(4-methoxyl group-phenyl oxygen the base)-5-fluoro-phenyl that in embodiment 143b, prepares]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.SFC separates (30%MeOH, 100par, 30 ℃), obtains required enantiomorph.
MS(M+H
+)，577。
Embodiment 147a
Preparation intermediate 6-chloro-3-(5-chloro-2-fluoro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-t-butyl formate
M.W?408.26，C
20H
16Cl
2FNO
3
With with the similar mode of the method for in embodiment 1a and 1b, describing, with 6-chloro-1,3-dihydro-indol-2-one (Aldrich) and the reaction of 5-chloro-2-fluoro-phenyl aldehyde, obtain 6-chloro-3-[1-(5-chloro-2-fluoro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles is used it (t-BuOCO) subsequently
2O and DMAP protection.
Embodiment 147b
Preparation chirality (2 ' R, 3 ' R, 4 ' R)-6-chloro-4 '-(5-chloro-2-fluoro-phenyl)-2 '-[5-fluoro-2-(4-methoxyl group-phenyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，595.43，C
31H
22Cl
2F
2N
2O
4
With with the similar mode of the method for in embodiment 1e, describing, with 6-chloro-3-[1-(3-fluoro-5-chloro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[2-(4-methoxyl group-phenyl oxygen the base)-5-fluoro-phenyl that in embodiment 143b, prepares]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.
SFC separates (30%MeOH, 100par, 30 ℃), obtains required enantiomorph.MS(M+H
+)，595。
Embodiment 148a
Preparation intermediate 4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenol
MW，268.43，C
14H
24O
3Si
To the quinhydrones that stirs (Aldrich, 11.01g is 100mmol) in the solution in DMF (300mL), adding (2-bromo-the oxyethyl group)-tertiary butyl-dimethyl-silane (Aldrich, 12.0g, 50mmol), (40.7g's cesium carbonate 125mol) and with mixture spends the night 60 ℃ of stirrings.Mixture is poured in the water (300mL) and added 6N HCl so that " pH " is adjusted to 6.With EtOAc (3x60mL) extraction mixture, extract is merged and drying.Remove and desolvate, obtain thick product,, obtain the light brown solid its chromatographic separation on the ISCO machine of using EtOAc/ hexane (0-30%) wash-out.5.71g。
Embodiment 148b
Preparation intermediate 5-fluoro-2-{4-[2-(tertiary butyl-dimethyl-silanyloxy base) oxyethyl group]-phenoxy group }-phenyl aldehyde
MW，390.53，C
21H
27FO
4Si
With with the similar mode of the method for in embodiment 140a, describing, make 2,4-two fluoro-phenyl aldehydes (Aldrich) and 4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenol and salt of wormwood reaction, obtain light brown oily thing, solidify when it leaves standstill.MS(H
+)，391。
Embodiment 148c
Preparation intermediate 1-[5-fluoro-2-{4-[2-(tertiary butyl-dimethyl-silanyloxy base) oxyethyl group]-phenoxy group }-phenyl]-3-TMS oxygen base-2-azepine-1,3-butadiene
MW，503.77，C
26H
38FNO
4Si
2
With with in the similar mode of method described in the embodiment 112b, with 5-fluoro-2-{4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenoxy group }-phenyl aldehyde LHMDS, Acetyl Chloride 98Min., triethylamine and chloro-trimethylammonium-silane treatment, obtain required compound, it is directly used in next step.
Embodiment 148d
Preparation racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-and 5-fluoro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group] phenyl }-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，609，C
32H
24ClF
3N
2O
5
With with the similar mode of the method for in embodiment 1e, describing; make the 6-chloro-3-[1-(2 that in embodiment 139b, prepares; 5-two fluoro-phenyl)-methylene radical]-2-oxo-2; 3-dihydro-indoles-1-t-butyl formate and 1-[5-fluoro-2-{4-[2-(tertiary butyl-dimethyl-silanyloxy base)-oxyethyl group]-phenoxy group } phenyl]-3-trimethylsiloxy-2-azepine-1; the reaction of 3-divinyl; then carry out deprotection reaction, obtain required product, be white solid with tetrabutyl ammonium fluoride.
MS(M+H
+)，609。
Embodiment 149
Preparation racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-4 '-(5-chloro-2-fluoro-phenyl)-2 '-and 5-fluoro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group] phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，625.45，C
32H
24Cl
2F
2N
2O
5
With with the similar mode of the method for in embodiment 1e, describing; make 6-chloro-3-[1-(2-fluoro-5-chloro-the phenyl)-methylene radical that in embodiment 147a, prepares]-2-oxo-2; 3-dihydro-indoles-1-t-butyl formate and 1-[5-fluoro-2-{4-[2-(tertiary butyl-dimethyl-silanyloxy the base)-oxyethyl group that in embodiment 148c, prepares]-phenoxy group } phenyl]-3-TMS oxygen base-2-azepine-1; the reaction of 3-divinyl; then carry out deprotection with tetrabutyl ammonium fluoride; obtain required product, be white solid.
MS(M+H
+)，625。
Embodiment 150
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-fluoro-phenyl)-2 '-and 5-fluoro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group] phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，591.01，C
32H
25ClF
2N
2O
5
With with the similar mode of the method for in embodiment 1e, describing; the 6-chloro-3-[1-that will in embodiment 129b, prepare (3-fluoro-phenyl)-methylene radical]-2-oxo-2; 3-dihydro-indoles-1-t-butyl formate and 1-[5-fluoro-2-{4-[2-(tertiary butyl-dimethyl-silanyloxy the base)-oxyethyl group that in embodiment 148c, prepares]-phenoxy group } phenyl]-3-trimethylsiloxy-2-azepine-1; the reaction of 3-divinyl; then use the tetrabutyl ammonium fluoride deprotection; obtain required product, be white solid.
MS(M+H
+)，591。
Embodiment 151
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-4 '-(3-chloro-phenyl)-6-fluoro-2 '-and 5-fluoro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group] phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW?591.01，C
32H
25ClF
2N
2O
5
With with the similar mode of the method for in embodiment 1e, describing; make 6-fluoro-3-[1-(3-chloro-the phenyl)-methylene radical that in embodiment 138b, prepares]-2-oxo-2; 3-dihydro-indoles-1-t-butyl formate and 1-[5-fluoro-2-{4-[2-(tertiary butyl-dimethyl-silanyloxy the base)-oxyethyl group that in embodiment 148c, prepares]-phenoxy group } phenyl]-3-TMS oxygen base-2-azepine-1; the reaction of 3-divinyl; then carry out deprotection reaction with tetrabutyl ammonium fluoride; obtain required product, be white solid.
MS(M+H
+)，591。
Embodiment 152
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-and 5-fluoro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group] phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，607.46，C
31H
23Cl
2FN
2O
4
With with the similar mode of the method for in embodiment 1e, describing; make 6-chloro-3-[1-(3-chloro-the phenyl)-methylene radical that in embodiment 1b, prepares]-2-oxo-2; 3-dihydro-indoles-1-t-butyl formate and 1-[5-fluoro-2-{4-[2-(tertiary butyl-dimethyl-silanyloxy the base)-oxyethyl group that in embodiment 148c, prepares]-phenoxy group } phenyl]-3-TMS oxygen base-2-azepine-1; the reaction of 3-divinyl; then carry out deprotection reaction with tetrabutyl ammonium fluoride; obtain required product, be white solid.
MS(M+H
+)，607。
Embodiment 153a
Preparation intermediate 6-chloro-3-[1-(2-chloro-5-trifluoromethyl-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate
M.W.458.27，C
21H
16Cl
2F
3NO
3
With with the similar mode of the method for in embodiment 1a and 1b, describing, make 6-chloro-1,3-dihydro-indol-2-one (Aldrich) and 2-chloro-5-trifluoromethyl-phenyl aldehyde (Aldrich) reaction, obtain 6-chloro-3-[1-(2-chloro-5-trifluoromethyl-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles, it is subsequently with dimethyl dicarbonate butyl ester and DMAP reaction and be directly used in next step.
Embodiment 153b
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-4 '-(5-chloro-2-trifluoromethyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，639.89，C
30H
24Cl
3FN
2O
4
With with the similar mode of the method for in embodiment 1e, describing, make 6-chloro-3-[1-(3-chloro-2-trifluoromethyl-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and the 1-[5-chloro-2-that in embodiment 99b, prepares (tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-trimethylsiloxy-2-azepine-1, the reaction of 3-divinyl obtains required product.
MS(M+H
+)，639。
Embodiment 154a
Preparation intermediate 1-[5-iodo-2-(cyclohexyl oxygen base)-phenyl]-3-TMS oxygen base-2-azepine-1,3-butadiene
MW，443.4，C
18H
26INO
2Si
With with the similar mode of the method for in embodiment 128a and 112b, describing, make the reaction of 5-iodo-2-hydroxyl-phenyl aldehyde and methylsulfonic acid cyclohexyl and salt of wormwood, obtain 5-iodo-2-(cyclohexyl oxygen base)-phenyl aldehyde, make itself and LHMDS subsequently, Acetyl Chloride 98Min., triethylamine and trimethylammonium-chlorosilane reaction obtains title compound and is directly used in next step.
Embodiment 154b
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(5-chloro-2-trifluoromethyl-phenyl)-2 '-[5-iodo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，731.34，C
30H
24Cl
2F
3IN
2O
4
With with the similar mode of the method for in embodiment 1e, describing, make 6-chloro-3-[1-(3-chloro-2-trifluoromethyl-phenyl)-methylene radical that in embodiment 153a, prepares]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[5-iodo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.
MS(M+H
+)，731。
Embodiment 155
Preparation (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(5-chloro-2-trifluoromethyl-phenyl)-2 '-[2-(cyclohexyl oxygen base)-5-fluoro-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，621.46，C
31H
26Cl
2F
4N
2O
3
With with the similar mode of the method for in embodiment 1e, describing, make 6-chloro-3-[1-(3-chloro-2-trifluoromethyl-phenyl)-methylene radical that in embodiment 153a, prepares]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[2-(cyclohexyl oxygen the base)-5-fluoro-phenyl that in embodiment 132c, prepares]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.
MS(M+H
+)，621。
Embodiment 156
Preparation chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，555.44，C
29H
25Cl
2FN
2O
4
With with the similar mode of the method for in embodiment 1e, describing, make 6-chloro-3-[1-(3-fluoro-the phenyl)-methylene radical that in embodiment 129b, prepares]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and the 1-[5-chloro-2-that in embodiment 99b, prepares (tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.MS(M+H
+)，555。
Chirality SFC separates (30%MeOH, 100Par, 30 ℃), obtains required enantiomorph.MS(M+H
+)，555。
Embodiment 157
Preparation chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-fluoro-2-(cyclopentyloxy)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，522.98，C
29H
25ClF
2N
2O
3
With with the similar mode of the method for in embodiment 1e, describing, make 6-chloro-3-[1-(3-fluoro-the phenyl)-methylene radical that in embodiment 129b, prepares]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[5-fluoro-2-(the cyclopentyloxy)-phenyl that in embodiment 133c, prepares]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.MS(M+H
+)，523。
With racemoid on SFC at 30%MeOH, further separate under 100Par and 30 ℃ the condition, obtain enantiomorph.
MS(M+H
+)，523。
Embodiment 158
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[2-(cyclohexyl oxygen base-5-iodine)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，644.91，C
30H
27ClFIN
2O
3
With with the similar mode of the method for in embodiment 1e, describing, make 6-chloro-3-[1-(3-fluoro-the phenyl)-methylene radical that in embodiment 129b, prepares]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[2-(cyclohexyl oxygen base-5-the iodine)-phenyl that in embodiment 154a, prepares]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.
MS(M+H
+)，645。
Embodiment 159
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[2-(cyclohexyl oxygen base-5-fluorine)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，537.00，C
30H
27ClF
2N
2O
3
With with the similar mode of the method for in embodiment 1e, describing, make 6-chloro-3-[1-(3-fluoro-the phenyl)-methylene radical that in embodiment 129b, prepares]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[2-(cyclohexyl oxygen base-5-the fluorine)-phenyl that in embodiment 132c, prepares]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.
MS(M+H
+)，537。
Embodiment 160
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[2-(cyclohexyl oxygen base-5-ethynyl)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，543.03，C
32H
28ClFN
2O
3
To in embodiment 158, preparing racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[2-(cyclohexyl oxygen base-5-iodine)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2, (100mg is 0.16mmol) in the solution that is stirring in DMF (3mL) for 6 '-diketone, add trimethyl silyl acetylene (Aldrich, 220uL, 1.55mmol), PdCl
2(PPh
3)
2(Aldrich, 5mg, 0.07mmol), CuI (Aldrich, 1mg) and Et
3N (1mL), and mixture stirred 3h in 65 ℃ under nitrogen.Mixture is poured in the water, and new blend is extracted with EtOAc (3x10mL), use dried over sodium sulfate.Solvent removed and resistates is gone up purifying at ISCO machine (2%EtOAc/ methylene dichloride), obtain pale solid.With pale solid the NaOH aqueous solution (2N, 3mL) and in the mixture of methyl alcohol (3mL) in stirring at room 2h.Mixture is acidified to " pH " 5 and with solid filtering and drying.50.8mg.MS(M+H
+)，543。
Embodiment 161
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-[2-(cyclohexyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，661.36，C
30H
27Cl
2IN
2O
3
With with the similar mode of the method for in embodiment 1e, describing, make 6-chloro-3-[1-(3-chloro-the phenyl)-methylene radical that in embodiment 1b, prepares]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[2-(cyclohexyl oxygen base-5-the iodine)-phenyl that in embodiment 132c, prepares]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.
MS(M+H
+)，661。
Embodiment 162
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-[2-(cyclohexyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，543.03，C
32H
28Cl
2N
2O
3
With with the similar mode of in embodiment 160, describing of method, make racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-[2-(cyclohexyl oxygen base-5-iodine)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone and trimethyl silyl acetylene, PdCl
2(PPh
3)
2, CuI and Et
3The N reaction is then reacted with NaOH in methyl alcohol, obtains white solid.
MS(M+H
+)，543。
Embodiment 163
Preparation racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[5-chloro-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，589.49，C
29H
24Cl
2F
2N
2O
3S
With with the similar mode of the method for in embodiment 1e, describing, make the 6-chloro-3-[1-(2 that in embodiment 139b, prepares, 5-two fluoro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and the 1-[5-chloro-2-that in embodiment 135b, prepares (tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.
MS(M+H
+)，589。
Embodiment 164
Preparation chirality (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[2-cyclohexyl oxygen base-5-fluoro-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，554.99，C
29H
24ClF
3N
2O
3S
With with the similar mode of the method for in embodiment 1e, describing, make the 6-chloro-3-[1-(2 that in embodiment 139b, prepares, 5-two fluoro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[5-fluoro-2-(cyclohexyl oxygen the base)-phenyl that in embodiment 132c, prepares]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.Chirality SFC separates (30%MeOH, 100Par, 30 ℃), obtains required enantiomorph.
MS(M+H
+)，555。
Embodiment 165
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-2 '-[5-chloro-2-(cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl)-6-fluorine spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，553.46，C
30H
27Cl
2N
2O
3
With with the similar mode of the method for in embodiment 1e, describing, make 6-fluoro-3-[1-(3-chloro-the phenyl)-methylene radical that in embodiment 138b, prepares]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[5-chloro-2-(cyclohexyl oxygen the base)-phenyl that in embodiment 134b, prepares]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains white solid.
MS(M+H
+)，553。
Embodiment 166
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-4 '-(3-chloro-phenyl)-2 '-[5-chloro-2-(tetrahydrochysene-thiapyran-4-base oxygen base-phenyl)]-6-fluorine spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，571.50，C
29H
25FCl
2N
2O
3S
With with the similar mode of the method for in embodiment 1e, describing, make 6-fluoro-3-[1-(3-chloro-the phenyl)-methylene radical that in embodiment 138b, prepares]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and the 1-[5-chloro-2-that in embodiment 135b, prepares (tetrahydrochysene-thiapyran-4-base oxygen base-phenyl]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains white solid.
MS(M+H
+)，571。
Embodiment 167
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(cyclohexyl oxygen base-phenyl)]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，553.46，C
30H
27Cl
2N
2O
3
With with the similar mode of the method for in embodiment 1e, describing, make 6-chloro-3-[1-(3-fluoro-the phenyl)-methylene radical that in embodiment 129b, prepares]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and 1-[5-chloro-2-(cyclohexyl oxygen the base)-phenyl that in embodiment 134b, prepares]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains white solid.
MS(M+H
+)，553。
Embodiment 168
Preparation chirality (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，573.42，C
29H
24Cl
2F
2N
2O
3
With with the similar mode of the method for in embodiment 1e, describing, make the 6-chloro-3-[1-(2 that in embodiment 139b, prepares, 5-two fluoro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and the 1-[5-chloro-2-that in embodiment 99b, prepares (tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.Chirality SFC separates (30%MeOH, 100Par, 30 ℃), obtains required enantiomorph.
MS(M+H
+)，573
Embodiment 169
Preparation chirality (2 ' R, 3 ' R, 4 ' R)-6-chloro-4 '-(2,5-two fluoro-phenyl)-2 '-[5-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone
MW，573.42，C
29H
24ClF
3N
2O
3
With with the similar mode of the method for in embodiment 1e, describing, make the 6-chloro-3-[1-(2 that in embodiment 139b, prepares, 5-two fluoro-phenyl)-methylene radical]-2-oxo-2,3-dihydro-indoles-1-t-butyl formate and the 1-[5-fluoro-2-that in embodiment 128b, prepares (tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-3-TMS oxygen base-2-azepine-1, the reaction of 3-divinyl obtains required product.Chirality SFC separates (30%MeOH, 100Par, 30 ℃), obtains required enantiomorph.MS(M+H
+)，557。
Embodiment 170
Activity test in vitro
Test by HTRF (homogeneous phase time discrimination fluorescence), measure compound and suppress interactional ability between p53 and the MDM2 albumen, in HTRF (homogeneous phase time discrimination fluorescence) test, the MDM2 of reorganization GST-mark is attached on the peptide, and described peptide is similar to the MDM2-interaction area (Lane etc.) of p53.The combination of GST-MDM2 albumen and p53-peptide (at biotinylation on its N-end) is by FRET (fluorescence resonance energy transmission) record between the allophycocyanin (APC) of anti--GST antibody of europium (Eu)-mark and chain enzyme antibiotin-put together.
At cumulative volume is 40uL; accommodate: 90nM biotinylation peptide; 160ng/mlGST-MDM2; 20nM chain enzyme antibiotin-APC (PerkinElmerWallac); anti--GST-the antibody (PerkinElmerWallac) of 2nM Eu-mark; 0.2% bovine serum albumin(BSA) (BSA); in the flat 384-orifice plate of black (Costar) of 1mM dithiothreitol (DTT) (DTT) and 20mM Tris-borate salt solution (TBS) damping fluid, the following test: the GST-MDM2 (640ng/ml working solution) of 10uL in reaction buffer joined in each hole.The compound (diluting with 1: 5 in reaction buffer) of 10uL dilution is joined in each hole, mix by vibration.The biotinylation p53 peptide (180nM working solution) of 20uL in reaction buffer joined in each hole, and on vibrator, mix.In 37 ℃ of incubation 1h.Adding chain enzyme antibiotin-APC and the Eu-of 20uL in containing the TBS damping fluid of 0.2%BSA resists-GST mixtures of antibodies (6nM Eu-resists-GST and 60nM chain enzyme antibiotin-APC working solution), in room temperature vibration 30 minutes, and use can TRF plate reader in 665 and 615nm (Victor 5, PerkinElmerWallac) reading.If do not specify, reagent is available from Sigma chemistry company limited (SigmaChemical Co.).
Show described bioactive IC of the present invention
50Show the activity that is lower than about 10 μ M.
Representative value for example has:
Embodiment
IC
50
(μ M, 0.02%BSA)
2 0.205
5c 0.034
22b 0.042
56 0.131
87 0.048
Claims (26)
1. the compound of formula (I),
Wherein
X is-Cl ,-F or-Br;
R is the phenyl of replacement or the heteroaryl of replacement, and wherein the heteroaryl of phenyl of Qu Daiing or replacement is selected from the group of being made up of following:
W is selected from the group of being made up of following :-F ,-Cl ,-Br ,-I, methyl, ethyl, cyclopropyl, cyano group, methoxyl group, methylol ,-COOMe, ethynyl ,-CF
3, vinyl, pseudoallyl, 1-proyl, 3-methyl isophthalic acid-butynyl, 3,3-dimethyl-ethyl acetylene base, 3-trifluoro ethynyl, phenyl, 2-furyl, 2-thienyl and 4-thiazolyl;
Y is a hydrogen ,-F ,-Cl or methyl;
V is a hydrogen ,-F ,-Cl or methyl;
A is selected from the group of being made up of following: key, O, NH, CH
2, C (=O), C (=O) NH, NHC (=O), NHC (=O) NH, S, S (=O)
2And O (CH
2)
n
N=1,2 or 3;
R ' is selected from the group of being made up of following: heterocycle, the heterocycle of replacement, heteroaryl, the heteroaryl of replacement, aryl, the aryl of replacement, the cycloalkyl of replacement and-CR
1R
2C (=O) NR
3R
4, wherein
R
1, R
2Be hydrogen or low alkyl group, or can separate connection with formation be selected from replacement or
The ring texture of unsubstituted cycloalkyl; And
R
3, R
4Be independently selected from the group of forming by following: hydrogen, low alkyl group, aryl, low-grade alkenyl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle of replacement, the cycloalkyl of cycloalkyl and replacement, condition are R
3, R
4Not all be hydrogen, or R
3/ R
4Can separate connection to form ring texture, described ring texture is selected from heteroaryl replacement or unsubstituted, cycloalkyl replacement or unsubstituted, cycloalkenyl group replacement or unsubstituted or replacement or unsubstituted heterocycle; With
Its pharmaceutical salts and ester.
2. the described compound of claim 1, W wherein, X, Y, A, R and R ' described in claim 1 and V be hydrogen or F.
3. the described compound of claim 1, W wherein, X, A, R and R ' are described in claim 1, and V is that hydrogen or F and Y are hydrogen or F.
4. the described compound of claim 1, X wherein, A, R and R ' are described in claim 1, and W is F, and Cl, Br, I or ethynyl, Y are that hydrogen or F and V are hydrogen or F.
5. the described compound of claim 1, X wherein, R and R ' are described in claim 1, and W is F, Cl, Br, I or ethynyl, Y are hydrogen or F, and V is that hydrogen or F and A are O or NH, and condition is that Y and V not all are F.
6. the described compound of claim 1, wherein
R is the 3-chloro-phenyl-;
A is-O-or-NH-;
R ' is a piperidyl, tetrahydrochysene-pyranyl, and cyclohexyl, pyrrolidyl, phenyl, pyrazinyl and pyrazolyl, they all can be unsubstituted or be replaced by 1-5 substituting group; And
All remaining substituting groups have the implication that provides in the claim 1.
7. the described compound of claim 1, it is selected from the group of being made up of following:
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl methoxy base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl methoxy base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl methoxy base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl amino)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl amino)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
8. the described compound of claim 1, it is selected from the group of being made up of following:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-propionyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[1-(3-methylsulfonyl-propyl group)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methylsulfonyl-4-piperidyl oxygen base) phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-methylsulfonyl-4-piperidyl oxygen base) phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-formyl-dimethylamino-4-piperidyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-bromo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-4-piperidyl oxygen base)-5-bromo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[6-(1-ethanoyl-4-piperidyl oxygen base)-3-bromo-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-ethyl-4-piperidyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-2-fluoro-6-(1-methyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Chirality (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-2-fluoro-6-(1-methyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
9. the described compound of claim 1, it is selected from the group of being made up of following:
Racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-formyl-dimethylamino-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-formyl-dimethylamino-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-diethylamino formyl radical-4-piperidyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-iodo-2-[1-(tetramethyleneimine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[1-(tetramethyleneimine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1-sec.-propyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[1-(2-oxo-imidazolidine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[6-(1-(tertbutyloxycarbonyl)-4-piperidyl oxygen base)-3-chloro-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[6-(1-ethanoyl-4-piperidyl oxygen base)-3-chloro-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[3-chloro-6-(1-formyl-dimethylamino-4-piperidyl oxygen base)-2-fluoro-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[3-chloro-6-(1-methylamino formyl radical-4-piperidyl oxygen base)-2-fluoro-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-6-(1-methylamino formyl radical-4-piperidyl oxygen base)-2-fluoro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-formyl-dimethylamino-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
10. the described compound of claim 1, it is selected from the group of being made up of following:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[1-(4-methylpiperazine-1-carbonyl)-4-piperidyl oxygen base]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[1-(1-tetramethyleneimine-carbonyl)-4-piperidyl oxygen base]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[1-(1-tetramethyleneimine-carbonyl)-4-piperidyl oxygen base]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-formyl-dimethylamino-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-ethoxy carbonyl-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-ethoxy carbonyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-isobutyryl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-isopropoxy carbonyl-4-piperidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
11. the described compound of claim 1, it is selected from the group of being made up of following:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-isobutyryl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-isopropoxy carbonyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2-[1-(2-hydroxyl-ethyl)-4-piperidyl oxygen base]-5-iodo-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1-methoxycarbonyl methyl-4-piperidyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-tertiary butyloxycarbonyl ylmethyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(1-hydroxycarbonyl group methyl-4-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-carbamyl ylmethyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(1-carbamyl ylmethyl-4-piperidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-tertbutyloxycarbonyl-3-pyrrolidyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-tertbutyloxycarbonyl-3-pyrrolidyl oxygen base)-5-iodo-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-methoxyl group-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
12. the described compound of claim 1, it is selected from the group of being made up of following:
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2,5-dimethyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-methoxyl group-4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-hydroxycarbonyl group-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[4-(2-hydroxyl-1,1-dimethyl-ethylamino formyl radical)-phenoxy group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[4-(2-tetramethyleneimine-1-base-ethylamino formyl radical)-phenoxy group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-formamyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-chloro-4-methoxycarbonyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methoxycarbonyl-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-5-iodo-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-5-iodo-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-5-ethynyl-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-{ 5-chloro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl }-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-5-chloro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group]-phenyl }-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
13. the described compound of claim 1, it is selected from the group of being made up of following:
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2,6-dimethyl-4-pyridyl oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(5-chloro-2-imidazoles-1-base-phenyl)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-cyano group-phenoxy group)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-methoxyl group-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-methoxyl group-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-methoxyl group-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(4-methoxycarbonyl-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(4-methoxycarbonyl-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(4-hydroxycarbonyl group-phenoxy group)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(4-formamyl-phenoxy group)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(4-formamyl-phenoxy group)-5-ethynyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
14. the described compound of claim 1, it is selected from the group of being made up of following:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2,6-dimethyl-4-pyridyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2,6-dimethyl-4-pyridyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-fluoro-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-trifluoromethyl-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(4-trifluoromethyl-phenoxy group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(3-cyano group-phenoxy group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[4-(3-hydroxyl-propyl group)-phenoxy group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-cyano group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-cyano group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methylthio group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methyl sulphonyl-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-methylsulfinyl-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-nitro-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(4-amino-phenoxy group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
15. the described compound of claim 1, it is selected from the group of being made up of following:
Chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(4-amino-phenoxy group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(4-acetylamino-phenoxy group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-iodo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(1,3,5-trimethylammonium-1H-pyrazoles 4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1,3,5-trimethylammonium-1H-pyrazoles-4-base oxygen base)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(4-oxo-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3R, 4 ' S)-6-chloro-2 '-[2-chloro-6-(4-methoxyl group-phenoxy group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(cis-4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(cis-4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(trans-the 4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(trans-the 4-hydroxyl-cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-4-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
16. the described compound of claim 1, it is selected from the group of being made up of following:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-4-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-4-methyl-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(2,2,6,6-tetramethyl--tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' R)-6-chloro-4 '-(3-chloro-2-fluoro-phenyl)-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' R)-6-chloro-4 '-(3-chloro-4-fluoro-phenyl)-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[2-(4-ethanoyl-piperazine-1-yl)-1,1-dimethyl-2-oxo-oxyethyl group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[2-(4,4-two fluoro-piperidines-1-yl)-1,1-dimethyl-2-oxo-oxyethyl group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-5-bromo-2-[1-methyl isophthalic acid-(2,2,2-three fluoro-ethylamino formyl radicals)-oxyethyl group]-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-formyl-dimethylamino-1-methyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-formyl-dimethylamino-2-methyl-propoxy-)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2,2-dimethyl-3-oxo-3-tetramethyleneimine-1-base-propoxy-)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(3-methyl-trimethylene oxide-3-ylmethoxy)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
17. the described compound of claim 1, it is selected from the group of being made up of following:
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-bromo-2-(3-methyl-trimethylene oxide-3-ylmethoxy) phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(4-fluoro-benzyloxy)-phenyl]-6-chloro-4 ' (3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(3-ethyl-trimethylene oxide-3-ylmethoxy)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(1-tertbutyloxycarbonyl-piperidin-4-yl oxygen base)]-5-trifluoromethyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(1-methyl-piperidin-4-yl amino)-phenyl]-6-chloro-4 '-(5-chloro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2-hydroxyl-oxyethyl group)-5-(2-thienyl)-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2-hydroxyl-oxyethyl group)-5-(2-furyl)-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2-hydroxyl-oxyethyl group)-5-phenyl-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-2-(2-pyrazinyl oxygen base)-phenyl]-spiral shell-[3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-(2-furyl)-2-hydroxyl-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-(2-thio-furan base)-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-phenyl]-phenyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone and
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-(2-thiazolyl)-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone.
18. the described compound of claim 1, it is selected from the group of being made up of following:
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-hydroxyl-5-(2-thiazolyl)-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-2-[3-(tertbutyloxycarbonyl)-pyrroles's alkoxyl group]-5-chloro-phenyl }-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 ' piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-chloro-(3-pyrroles's alkoxyl group)-phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(3-methylsulfonyl-pyrroles's alkoxyl group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(3-ethylamino formyl radical-pyrroles's alkoxyl group)-phenyl }-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-[2-(1-ethanoyl-3-pyrroles's alkoxyl group)-5-chloro-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[trans-4-(3-hydroxyl-1-methylsulfonyl-piperidyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-[5-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-fluoro-phenyl)-2 '-[5-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(1,1-dioxo-tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(cyclohexyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(cyclopentyloxy)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone and
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(cyclohexyl oxygen base-phenyl)]-4 '-(3-chloro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone.
19. the described compound of claim 1, it is selected from the group of being made up of following:
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chlorine 2 '-[5-chloro-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl]-4 '-(3-fluoro-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(1,1-dioxo-tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-fluoro-phenyl)-2 '-[5-fluoro-2-(4-fluoro-phenoxy group-phenyl)] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-4 '-(3-chloro-phenyl)-6-fluoro-2 '-[2-(2,4-two fluoro-phenyl oxygen bases)-5-fluoro-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[5-chloro-2-(2-chloro-6-fluoro-benzyloxy)-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[2-(4-cyano group-phenyl oxygen base)-5-fluoro-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[2-(4-cyano group-phenyl oxygen base)-5-fluoro-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-4 '-(3-chloro-phenyl)-2 '-[2-(4-cyano group-phenyl oxygen base)-5-fluoro-phenyl]-6-fluorine spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-fluoro-2-(4-methoxyl group-phenyl oxygen base)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-4 '-(3-chloro-phenyl)-6-fluoro-2 '-[5-fluoro-2-(4-methoxyl group-phenyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[5-fluoro-2-(4-methoxyl group-phenyl oxygen base)-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-[5-fluoro-2-(4-methoxyl group-phenyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' R)-6-chloro-4 '-(5-chloro-2-fluoro-phenyl)-2 '-[5-fluoro-2-(4-methoxyl group-phenyl oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone and
Racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-and 5-fluoro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group] phenyl }-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone.
20. the described compound of claim 1, it is selected from the group of being made up of following:
Racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-4 '-(5-chloro-2-fluoro-phenyl)-2 '-and 5-fluoro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group] phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-fluoro-phenyl)-2 '-and 5-fluoro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group] phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-4 '-(3-chloro-phenyl)-6-fluoro-2 '-and 5-fluoro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group] phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-and 5-fluoro-2-[4-(2-hydroxyl-oxyethyl group)-phenoxy group] phenyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-4 '-(5-chloro-2-trifluoromethyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(5-chloro-2-trifluoromethyl-phenyl)-2 '-[5-iodo-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
(2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(5-chloro-2-trifluoromethyl-phenyl)-2 '-[2-(cyclohexyl oxygen base)-5-fluoro-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-fluoro-2-(cyclopentyloxy)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[2-(cyclohexyl oxygen base-5-iodine)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[2-(cyclohexyl oxygen base-5-fluorine)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[2-(cyclohexyl oxygen base-5-ethynyl)-phenyl]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-[2-(cyclohexyl oxygen base)-5-iodo-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone and
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-[2-(cyclohexyl oxygen base)-5-ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone.
21. the described compound of claim 1, it is selected from the group of being made up of following:
Racemize (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[5-chloro-2-(tetrahydrochysene-thiapyran-4-base oxygen base)-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[2-cyclohexyl oxygen base-5-fluoro-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-2 '-[5-chloro-2-(cyclohexyl oxygen base)-phenyl]-4 '-(3-chloro-phenyl)-6-fluorine spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-4 '-(3-chloro-phenyl)-2 '-[5-chloro-2-(tetrahydrochysene-thiapyran-4-base oxygen base-phenyl)]-6-fluorine spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(cyclohexyl oxygen base-phenyl)]-4 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone,
Chirality (2 ' R, 3 ' R, 4 ' R)-6-chloro-2 '-[5-chloro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl]-4 '-(2,5-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone and
Chirality (2 ' R, 3 ' R, 4 ' R)-6-chloro-4 '-(2,5-two fluoro-phenyl)-2 '-[5-fluoro-2-(tetrahydrochysene-pyrans-4-base oxygen base)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 '-diketone.
22. a pharmaceutical composition, it comprises according to any one described compound in the claim 1 to 21, and pharmaceutical carrier or vehicle.
23. as medicine according to any one described compound in the claim 1 to 21.
24. as medicine according to any one described compound in the claim 1 to 21, described medicine is used for the treatment of cancer, particularly solid tumor, mammary gland, colon, lung and tumor of prostate more specifically.
25. be used for the treatment of cancer according to any one described compound in the claim 1 to 21 in preparation, particularly solid tumor, the application in the medicine of mammary gland, colon, lung and tumor of prostate more specifically.
26. aforesaid basically new compound, method, technology and application.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1369107P | 2007-12-14 | 2007-12-14 | |
| US61/013,691 | 2007-12-14 | ||
| US10743108P | 2008-10-22 | 2008-10-22 | |
| US61/107,431 | 2008-10-22 | ||
| PCT/EP2008/066874 WO2009077357A1 (en) | 2007-12-14 | 2008-12-05 | Spiroindolinone derivatives |
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| Publication Number | Publication Date |
|---|---|
| CN101896486A true CN101896486A (en) | 2010-11-24 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2008801198987A Pending CN101896486A (en) | 2007-12-14 | 2008-12-05 | Spiroindolinone derivatives |
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| Country | Link |
|---|---|
| US (1) | US8134001B2 (en) |
| EP (1) | EP2229396B1 (en) |
| JP (1) | JP2011506380A (en) |
| KR (1) | KR20100076037A (en) |
| CN (1) | CN101896486A (en) |
| AT (1) | ATE519764T1 (en) |
| AU (1) | AU2008337651A1 (en) |
| BR (1) | BRPI0821255A2 (en) |
| CA (1) | CA2707456A1 (en) |
| IL (1) | IL205354A0 (en) |
| MX (1) | MX2010006107A (en) |
| WO (1) | WO2009077357A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321095A (en) * | 2011-05-26 | 2012-01-18 | 兰州大学 | Chiral spiro indole-pyran pyridine alkaline compound and preparation and application thereof |
| CN102584835A (en) * | 2011-01-17 | 2012-07-18 | 苏州大学 | Spiral heterocyclic compound containing indole structure and method for preparing same |
| CN102627650A (en) * | 2012-03-08 | 2012-08-08 | 徐州师范大学 | Chiral spiro(pyrrolidine-3, 2'-oxindole)compound and synthesis method thereof |
| CN116253736A (en) * | 2023-01-06 | 2023-06-13 | 中山大学 | Pyrazole beta-lactam derivative and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7776875B2 (en) * | 2007-12-19 | 2010-08-17 | Hoffman-La Roche Inc. | Spiroindolinone derivatives |
| US8354444B2 (en) * | 2008-09-18 | 2013-01-15 | Hoffmann-La Roche Inc. | Substituted pyrrolidine-2-carboxamides |
| UA107814C2 (en) | 2009-11-12 | 2015-02-25 | Дзе Ріджентс Оф Дзе Юніверсіті Оф Мічіган | Spiro-oxindoles antagonists mdm 2 |
| US8288431B2 (en) * | 2010-02-17 | 2012-10-16 | Hoffmann-La Roche Inc. | Substituted spiroindolinones |
| EP2638046A4 (en) | 2010-11-12 | 2014-06-25 | Univ Michigan | Spiro-oxindole mdm2 antagonists |
| JP5792279B2 (en) | 2011-03-10 | 2015-10-07 | 第一三共株式会社 | Dispiropyrrolidine derivatives |
| BR112013028983A2 (en) | 2011-05-11 | 2017-02-07 | Sanofi Sa | mdm2 antagonists spiro-oxindole |
| WO2013049250A1 (en) * | 2011-09-27 | 2013-04-04 | Amgen Inc. | Heterocyclic compounds as mdm2 inhibitors for the treatment of cancer |
| TWI586668B (en) | 2012-09-06 | 2017-06-11 | 第一三共股份有限公司 | Crystals of dispiropyrrolidine derivative |
| WO2015027067A2 (en) * | 2013-08-23 | 2015-02-26 | Virginia Commonwealth University | Ester nitrates derivatives of aromatic aldehydes with multiple pharmalogic properties to treat sickle cell disease |
| EP3164401B1 (en) | 2014-07-03 | 2018-12-26 | Boehringer Ingelheim International GmbH | New spiro[3h-indole-3,2´-pyrrolidin]-2(1h)-one compounds and derivatives as mdm2-p53 inhibitors |
| EP3260119B1 (en) | 2015-02-20 | 2023-11-15 | Daiichi Sankyo Company, Limited | Combination method for treating cancer |
| EP3284466A4 (en) | 2015-04-13 | 2018-12-05 | Daiichi Sankyo Company, Limited | Treatment method combining mdm2 inhibitor and btk inhibitor |
| MX2018004207A (en) | 2015-10-09 | 2018-07-06 | Boehringer Ingelheim Int | SPIRO[3H-INDOLE-3,2í´-PYRROLIDIN]-2(1H)-ONE COMPOUNDS AND DERIVATIVES AS MDM2-P53 INHIBITORS. |
| ES2858151T3 (en) | 2016-05-20 | 2021-09-29 | Hoffmann La Roche | PROTAC-Antibody Conjugates and Procedures for Use |
| WO2018074387A1 (en) | 2016-10-17 | 2018-04-26 | 第一三共株式会社 | Combination therapy method using mdm2 inhibitor and dna methyltransferase inhibitor |
| CN113543852A (en) | 2019-03-06 | 2021-10-22 | 第一三共株式会社 | Pyrrolopyrazole derivatives |
| WO2023056069A1 (en) | 2021-09-30 | 2023-04-06 | Angiex, Inc. | Degrader-antibody conjugates and methods of using same |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7495007B2 (en) * | 2006-03-13 | 2009-02-24 | Hoffmann-La Roche Inc. | Spiroindolinone derivatives |
| BRPI0708883A2 (en) | 2006-03-13 | 2011-06-14 | Hoffmann La Roche | spiroindolinone derivatives |
| US20070213341A1 (en) * | 2006-03-13 | 2007-09-13 | Li Chen | Spiroindolinone derivatives |
| US7638548B2 (en) * | 2006-11-09 | 2009-12-29 | Hoffmann-La Roche Inc. | Spiroindolinone derivatives |
-
2008
- 2008-11-18 US US12/272,870 patent/US8134001B2/en not_active Expired - Fee Related
- 2008-12-05 EP EP08861848A patent/EP2229396B1/en not_active Not-in-force
- 2008-12-05 BR BRPI0821255-4A patent/BRPI0821255A2/en not_active IP Right Cessation
- 2008-12-05 CN CN2008801198987A patent/CN101896486A/en active Pending
- 2008-12-05 MX MX2010006107A patent/MX2010006107A/en unknown
- 2008-12-05 KR KR1020107011040A patent/KR20100076037A/en not_active Application Discontinuation
- 2008-12-05 WO PCT/EP2008/066874 patent/WO2009077357A1/en active Application Filing
- 2008-12-05 AT AT08861848T patent/ATE519764T1/en not_active IP Right Cessation
- 2008-12-05 CA CA2707456A patent/CA2707456A1/en not_active Abandoned
- 2008-12-05 JP JP2010537394A patent/JP2011506380A/en active Pending
- 2008-12-05 AU AU2008337651A patent/AU2008337651A1/en not_active Abandoned
-
2010
- 2010-04-26 IL IL205354A patent/IL205354A0/en unknown
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584835A (en) * | 2011-01-17 | 2012-07-18 | 苏州大学 | Spiral heterocyclic compound containing indole structure and method for preparing same |
| CN102321095A (en) * | 2011-05-26 | 2012-01-18 | 兰州大学 | Chiral spiro indole-pyran pyridine alkaline compound and preparation and application thereof |
| CN102627650A (en) * | 2012-03-08 | 2012-08-08 | 徐州师范大学 | Chiral spiro(pyrrolidine-3, 2'-oxindole)compound and synthesis method thereof |
| CN102627650B (en) * | 2012-03-08 | 2015-07-08 | 徐州师范大学 | Chiral spiro(pyrrolidine-3, 2'-oxindole)compound and synthesis method thereof |
| CN116253736A (en) * | 2023-01-06 | 2023-06-13 | 中山大学 | Pyrazole beta-lactam derivative and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| MX2010006107A (en) | 2010-06-25 |
| BRPI0821255A2 (en) | 2015-06-16 |
| EP2229396A1 (en) | 2010-09-22 |
| ATE519764T1 (en) | 2011-08-15 |
| IL205354A0 (en) | 2010-12-30 |
| CA2707456A1 (en) | 2009-06-25 |
| US20090156610A1 (en) | 2009-06-18 |
| WO2009077357A1 (en) | 2009-06-25 |
| KR20100076037A (en) | 2010-07-05 |
| JP2011506380A (en) | 2011-03-03 |
| US8134001B2 (en) | 2012-03-13 |
| EP2229396B1 (en) | 2011-08-10 |
| AU2008337651A1 (en) | 2009-06-25 |
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Inventor after: Ding Qingjie Inventor after: Jiang Nan Inventor after: Yang Song Inventor after: Zhang Jing Inventor after: Zhang Zhuming Inventor before: Ding Qingjie Inventor before: Jiang Nan Inventor before: Yang Song Inventor before: Zhang Jing Inventor before: Zhang Zhuming |
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Application publication date: 20101124 |